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

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Cross-Over Trial of Febuxostat and Topiroxostat for Hyperuricemia with Cardiovascular Disease (TROFEO Trial) Circ J 2017; 81: 1707 – 1712 ORIGINAL ARTICLE doi: 10.1253/circj.CJ-17-0438 Preventive Medicine Cross-Over Trial of Febuxostat and Topiroxostat for Hyperuricemia With Cardiovascular Disease (TROFEO Trial) Akira Sezai, MD, PhD; Kazuaki Obata; Keisuke Abe; Sakie Kanno; Hisakuni Sekino, MD, PhD 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 both drugs, significantly more patients required dose escalation during treatment with topiroxostat. There were no differ- ences in renal function, inflammatory and lipid markers between the 2 drugs. A biomarker of oxidative stress was significantly lower after 3 months of febuxostat compared with topiroxostat. Conclusions: Febuxostat causes more marked and more rapid reduction of s-UA than topiroxostat. With regard to the antioxidant effect, febuxostat was superior to topiroxostat after 3 months. The renal protective and anti-inflammatory effects of both drugs were also similar after 6 months of treatment. Thus, both of these agents were similarly effective for hyperuricemia in patients with cardio- vascular disease. Key Words: Febuxostat; Hyperuricemia; Topiroxostat yperuricemia was recently reported to be associ- to reduce UA more potently than allopurinol,7 while ated with hypertension, cardiovascular disease, topiroxostat has a similar effect to allopurinol.8 No study, H and chronic kidney disease (CKD).1,2 Allopurinol however, has compared febuxostat with topiroxostat. has long been regarded as a first-line drug for the treatment Accordingly, a clinical study was conducted to compare of hyperuricemia, but adverse reactions such as renal dys- febuxostat with topiroxostat and assess potential differ- function, Stevens-Johnson syndrome, and hypersensitivity ences in efficacy (TopiROxostat and FEbuxostat in a ran- vasculitis have been reported with allopurinol, and it is not domized, Open-label, cross-over trial for hyperuricemia sufficiently effective in some cases.3,4 In a comparative trial with cardiovascular disease (TROFEO trial). of febuxostat vs. allopurinol, we reported that febuxostat reduced serum uric acid (s-UA) earlier than allopurinol, Methods had a stronger renoprotective effect than allopurinol, and also had superior antioxidant and anti-inflammatory Study Protocol effects.5,6 Unlike allopurinol, febuxostat and topiroxostat The subjects were outpatients with cardiovascular dis- (a novel xanthine oxidase reductase [XOR] inhibitor) have ease and hyperuricemia in whom s-UA was controlled at a non-purine structure and are mainly metabolized in the ≤6 mg/dL by treatment with allopurinol or febuxostat. In liver. In addition, these agents are excreted in both the this study, patients were randomized by the envelop urine and feces. Accordingly, their impact on the kidney is method to receive treatment with either febuxostat (Teijin minimal, and dose adjustment depending on renal function Pharma, Tokyo, Japan) or topiroxostat (Sanwa Kagaku is not required, in contrast to allopurinol. These 2 drugs Kenkyusho, Aichi, Japan and Fujiyakuhin, Saitama, have different dosing regimens (once daily for febuxostat Japan) for 6 months, after which they switched to the other vs. twice daily for topiroxostat) and febuxostat is reported medication for another 6 months. Baseline data were Received April 24, 2017; accepted May 4, 2017; released online June 9, 2017 Time for primary review: 10 days Department of Cardiovascular Surgery, Nihon University School of Medicine, Tokyo (A.S.); Sekino Hospital, Tokyo (K.O., K.A., S.K., H.S.), Japan Clinical Trial Registration: UMIN (http://www.umin.ac.jp/), Study ID: UMIN000014771 Mailing address: Akira Sezai, MD, PhD, Department of Cardiovascular Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashi-ku, Tokyo 173-8610, Japan. E-mail: [email protected] ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.81, November 2017 1708 SEZAI A et al. Table 1. Patient Characteristics for allopurinol or one-quarter of that for topiroxostat. Topiroxostat was given twice daily (after breakfast and Characteristic Data dinner) at a dose two-fifths of that for allopurinol and n 55 4-fold that for febuxostat. During the study period, s-UA Age (years) 67.9±9.0 was measured at monthly intervals. If it was ≥6.0 mg/dL, (39–79) the dose of febuxostat was increased by 10 mg/day or that 43:12 Gender (M:F) of topiroxostat was increased by 40 mg/day. The dose was Basic disease increased up to a maximum of 60 mg/day for febuxostat or Ischemic heart disease 20 (36) 160 mg/day for topiroxostat. Exclusion criteria were (1) Valvular disease 23 (42) renal dysfunction with an estimated glomerular filtration Aortic disease 10 (18) rate (eGFR) ≤20 mL/min/1.73 m2; (2) hepatic dysfunction Others 2 (4) (aspartate aminotransferase [AST] >39 U/L or alanine Risk factors aminotransferase [ALT] >44 U/L); (3) treatment with mer- Diabetes mellitus 19 (35) captopurine hydrate or azathiopurine; (4) pregnancy; (5) Hypertension 45 (82) other reasons that made patients unsuitable for this study Dyslipidemia 40 (73) as judged by the attending physician. This study was con- ducted at Sekino Hospital, a logistical support hospital of Chronic kidney disease 39 (71) Nihon University Itabashi Hospital. The details of the Cerebrovascular disease 4 (7) study were explained to the patients and informed consent Obesity 7 (13) was obtained. Approval of the institutional review board Smoking 18 (33) was also obtained and the study was registered with Medication the Hospital Medical Information Network (study ID: ARB 29 (53) UMIN000014771). ACEI 4 (7) Renin inhibitor 6 (11) Endpoints Aldosterone blocker 29 (53) The primary endpoint was s-UA level after treatment. The Calcium antagonist 23 (42) secondary endpoints were as follows: serum creatinine β-blocker 38 (69) (s-Cr), eGFR, urinary albumin, cystatin-C, oxidized low- density lipoprotein (O-LDL), eicosapentaenoic acid/ara- Statin 40 (73) chidonic acid (EPA/AA) ratio, total cholesterol (T-cho), Furosemide 25 (45) triglycerides (TG), low-density lipoprotein (LDL), high- Febuxostat 47 (85) density lipoprotein (HDL), remnant-like particle-cholesterol Allopurinol 8 (15) (RLP-cho), high-sensitivity C-reactive protein (hs-CRP), Data given as n (%) or mean ± SEM (range). ACEI, angiotensin- B-type natriuretic peptide (BNP), and adverse reactions. converting enzyme inhibitor; ARB, angiotensin II receptor blocker. s-UA, s-Cr, eGFR, T-cho, TG, LDL, HDL, and LDL/HDL (L/H) were measured before the start of treatment as well as after every month of treatment, while urinary albumin, cystatin-C, O-LDL, EPA/AA ratio, and BNP were mea- sured before treatment and after 3 and 6 months of treat- ment. Adverse reactions were classified as acute attacks of gout, skin reactions, renal dysfunction (increase of s-Cr by ≥50%), hepatic dysfunction (increase of AST/ALT by ≥50%), gastrointestinal symptoms, and allergic reactions. Management of the reactions (discontinuation of the test drug, etc.) was decided by the attending physician. Statistical Analysis Measured values are expressed as mean ± SEM. Two-way analysis of variance (ANOVA) was used to compare param- eters between the febuxostat and topiroxostat groups, and P<0.05 was considered statistically significant. Results Patients Fifty-five patients were enrolled in this trial and their Figure 1. Study flowchart. baseline characteristics are listed in Table 1. There were no drop-outs and all patients completed the 1-year study period without complications. Although there was a differ- ence between the 2 groups with regard to the medications obtained prior to switching to febuxostat or topiroxostat used for hyperuricemia prior to the study, there were no and monitoring was continued for 6 months after switch- other differences in patient characteristics. Before study ing. initiation, 22 patients in the febuxostat group were receiv- At the time of switching medication, febuxostat was ing febuxostat and 4 were taking allopurinol, while 25 given once daily after breakfast at a dose one-tenth of that patients in the topiroxostat group were receiving febuxo- Circulation Journal Vol.81, November 2017 TROFEO Trial 1709 Table 2. Change in Renal Function, Lipid Parameters and hs-CRP Before 1 month 2 months 3 months 4 months 5 months 6 months treatment s-Cr (mg/dL) Febuxostat 1.28±0.58 1.24±0.58 1.19±0.59 1,22±0.58 1.21±0.59 1.22±0.65 1.20±0.54 Topiroxostat 1.19±0.53 1.21±0.55 1.21±0.47 1.22±0.56 1.23±0.54 1.24±0.64 1.30±0.68 eGFR (ml/min/1.73 m2) Febuxostat 45.6±2.1 47.2±2.0 47.4±1.9 47.6±2.0 47.7±2.2 47.4±2.0 45.3±2.1 Topiroxostat 49.0±2.0 47.7±2.0 47.9±2.0 48.1±2.1 47.3±2.1
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