Preventive Medicine
Cross-Over Trial of Febuxostat and Topiroxostat for Hyperuricemia With Cardiovascular Disease (TROFEO Trial)
2017 Volume 81 Issue 11 Pages 1707-1712
Details
2017 Volume 81 Issue 11 Pages 1707-1712
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 differences 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 cardiovascular disease.
Hyperuricemia 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 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).
The 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 obtained prior to switching to febuxostat or topiroxostat and monitoring was continued for 6 months after switching.
At the time of switching medication, febuxostat was given once daily after breakfast at a dose one-tenth of that for allopurinol or one-quarter of that for topiroxostat. Topiroxostat was given twice daily (after breakfast and dinner) at a dose two-fifths of that for allopurinol and 4-fold that for febuxostat. During the study period, s-UA was measured at monthly intervals. If it was ≥6.0 mg/dL, the dose of febuxostat was increased by 10 mg/day or that of topiroxostat was increased by 40 mg/day. The dose was increased up to a maximum of 60 mg/day for febuxostat or 160 mg/day for topiroxostat. Exclusion criteria were (1) renal dysfunction with an estimated glomerular filtration rate (eGFR) ≤20 mL/min/1.73 m2; (2) hepatic dysfunction (aspartate aminotransferase [AST] >39 U/L or alanine aminotransferase [ALT] >44 U/L); (3) treatment with mercaptopurine hydrate or azathiopurine; (4) pregnancy; (5) other reasons that made patients unsuitable for this study as judged by the attending physician. This study was conducted at Sekino Hospital, a logistical support hospital of Nihon University Itabashi Hospital. The details of the study were explained to the patients and informed consent was obtained. Approval of the institutional review board was also obtained and the study was registered with the Hospital Medical Information Network (study ID: UMIN000014771).
EndpointsThe primary endpoint was s-UA level after treatment. The secondary endpoints were as follows: serum creatinine (s-Cr), eGFR, urinary albumin, cystatin-C, oxidized low-density lipoprotein (O-LDL), eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio, total cholesterol (T-cho), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), remnant-like particle-cholesterol (RLP-cho), high-sensitivity C-reactive protein (hs-CRP), B-type natriuretic peptide (BNP), and adverse reactions. 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 measured before treatment and after 3 and 6 months of treatment. 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 AnalysisMeasured values are expressed as mean±SEM. Two-way analysis of variance (ANOVA) was used to compare parameters between the febuxostat and topiroxostat groups, and P<0.05 was considered statistically significant.
Fifty-five patients were enrolled in this trial and their 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 difference between the 2 groups with regard to the medications used for hyperuricemia prior to the study, there were no other differences in patient characteristics. Before study initiation, 22 patients in the febuxostat group were receiving febuxostat and 4 were taking allopurinol, while 25 patients in the topiroxostat group were receiving febuxostat and 4 were taking allopurinol. There was no significant difference in prior therapy for hyperuricemia (P=1.00). It was confirmed that all patients in both groups took the assigned medications correctly.
| Characteristic | Data |
|---|---|
| n | 55 |
| Age (years) | 67.9±9.0 (39–79) |
| Gender (M:F) | 43:12 |
| Basic disease | |
| Ischemic heart disease | 20 (36) |
| Valvular disease | 23 (42) |
| Aortic disease | 10 (18) |
| Others | 2 (4) |
| Risk factors | |
| Diabetes mellitus | 19 (35) |
| Hypertension | 45 (82) |
| Dyslipidemia | 40 (73) |
| Chronic kidney disease | 39 (71) |
| Cerebrovascular disease | 4 (7) |
| Obesity | 7 (13) |
| Smoking | 18 (33) |
| Medication | |
| ARB | 29 (53) |
| ACEI | 4 (7) |
| Renin inhibitor | 6 (11) |
| Aldosterone blocker | 29 (53) |
| Calcium antagonist | 23 (42) |
| β-blocker | 38 (69) |
| Statin | 40 (73) |
| Furosemide | 25 (45) |
| Febuxostat | 47 (85) |
| Allopurinol | 8 (15) |
Data given as n (%) or mean±SEM (range). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
There was no significant difference in s-UA between the 2 groups either before or after treatment. s-UA, however, did not exceed 6.0 mg/dL in the febuxostat group during the study period, but it exceeded this level in 9 patients from the topiroxostat group, with the number being significantly higher in the topiroxostat group (P=0.003; Figure 1). The dose of febuxostat was 16.5±9.7 mg at the initiation of treatment. No patient required dose escalation of febuxostat and the same dose was maintained for 6 months. The dose of topiroxostat was 59.6±33.5 mg at initiation of treatment, while it was 61.5±33.3 mg, 64.4±35.6 mg, 68.0±38.2 mg, 69.5±38.7 mg, 70.9±40.5 mg and 70.9±40.5 mg after 1, 2, 3, 4, 5 and 6 months, respectively.
Study flowchart.
s-Cr, eGFR There was no significant difference in s-Cr and eGFR between the 2 drugs either before or after treatment (Table 2; Figure 2).
| Before treatment |
1 month | 2 months | 3 months | 4 months | 5 months | 6 months | |
|---|---|---|---|---|---|---|---|
| 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 | 48.3±2.1 | 48.2±2.0 |
| T-cho (mg/dL) | |||||||
| Febuxostat | 163.9±4.0 | 162.9±4.0 | 164.0±4.0 | 165.0±4.3 | 167.4±4.0 | 164.2±3.9 | 160.2±3.7 |
| Topiroxostat | 159.8±4.0 | 160.0±3.9 | 160.1±4.0 | 163.1±4.0 | 166.4±4.1 | 163.2±4.1 | 161.5±4.3 |
| TG (mg/dL) | |||||||
| Febuxostat | 134.7±10.4 | 133.0±11.0 | 124.1±7.6 | 135.9±10.2 | 123.2±7.3 | 121.0±7.0 | 121.3±8.7 |
| Topiroxostat | 127.7±8.5 | 119.4±7.5 | 117.5±7.1 | 120.9±7.4 | 114.7±6.3 | 113.9±7.6 | 113.9±7.6 |
| L/H | |||||||
| Febuxostat | 1.62±0.90 | 1.62±0.84 | 1.62±0.84 | 1.66±0.92 | 1.65±0.10 | 1.55±0.86 | 1.57±0.85 |
| Topiroxostat | 1.63±0.81 | 1.60±0.80 | 1.60±0.82 | 1.57±0.82 | 1.58±0.81 | 1.56±0.80 | 1.54±0.84 |
| hs-CRP (mg/dL) | |||||||
| Febuxostat | 0.18±0.03 | 0.25±0.05 | 0.27±0.06 | 0.24±0.06 | 0.23±0.06 | 0.35±0.12 | 0.24±0.05 |
| Topiroxostat | 0.19±0.04 | 0.33±0.15 | 0.23±0.04 | 0.18±0.03 | 0.25±0.07 | 0.28±0.06 | 0.21±0.04 |
eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein; L/H, high-density lipoprotein/low-density lipoprotein; s-Cr, serum creatinine; T-cho, total cholesterol; TG, triglyceride.
Change in (Upper) serum uric acid (UA) and (Lower) number of patients with xanthine oxidase reductase (XOR) inhibitor add-on therapy (Lower).
Urinary Albumin There was no difference in urinary albumin prior to treatment with the 2 drugs, and no significant difference was observed after 3 or 6 months of treatment (3 months, P=0.369; 6 months, P=0.359; Figure 2).
Cystatin-C There was no difference in cystatin-C before treatment with the 2 drugs, as well as no significant difference after 3 or 6 months of treatment (3 months, P=0.359; 6 months, P=0.300; Table 3).
| Cystatin-C | Before treatment | 3 months | 6 months |
|---|---|---|---|
| Cystatin-C (mg/dL) | |||
| Febuxostat | 1.41±0.07 | 1.34±0.07 | 1.34±0.07 |
| Topiroxostat | 1.39±0.06 | 1.43±0.07 | 1.46±0.07 |
| EPA/AA | |||
| Febuxostat | 0.56±0.05 | 0.66±0.06 | 0.61±0.06 |
| Topiroxostat | 0.73±0.12 | 0.61±0.06 | 0.57±0.05 |
| RLP-cho (mg/dL) | |||
| Febuxostat | 5.31±0.48 | 5.17±0.47 | 4.69±0.46 |
| Topiroxostat | 5.20±0.50 | 5.51±0.43 | 5.05±0.37 |
| BNP (pg/mL) | |||
| Febuxostat | 107.7±22.8 | 96.3±21.0 | 98.5±23.5 |
| Topiroxostat | 91.7±22.8 | 102.6±22.9 | 120.9±26.4 |
BNP, B-type natriuretic peptide; EPA/AA, eicosapentaenoic acid/arachidonic acid; RLP-cho, remnant-like particle-cholesterol.
O-LDL There was no difference in O-LDL prior to treatment with the 2 drugs. O-LDL was significantly lower after 3 months of febuxostat treatment compared with topiroxostat (P=0.030), but there was no significant difference between the 2 drugs after 6 months of treatment (P=0.227; Figure 2).
EPA/AA There was no significant difference in EPA/AA ratio between the 2 drugs either before or after treatment (Table 3).
T-cho, TG, LDL, HDL, and L/H There were no significant differences in T-cho, TG, LDL, HDL, and L/H between the 2 drugs either before or after treatment (Table 2).
RLP-cho There was no significant difference in RLP-cho between the 2 drugs either before or after treatment (Table 3).
hs-CRP There was no significant difference in hs-CRP between the 2 drugs either before or after treatment (Table 2).
BNP There was no significant difference in BNP between the 2 drugs either before or after treatment (Table 3).
Other Parameters During the study period, none of the patients experienced adverse reactions and there were no attacks of gout while they were on treatment with either drug. Among the 28 patients taking warfarin, there were no bleeding events or strokes during the study period. Nine patients (32%), however, had an increase in international normalized ratio of prothrombin time (PT-INR) by ≥150% after switching from febuxostat to topiroxostat, and the dose of warfarin was reduced in all 9 patients. Conversely, 3 patients (11%) had a reduction of PT-INR by ≥150% after switching from topiroxostat to febuxostat. Prior to the study, there was no significant difference in PT-INR between patients using either drug. PT-INR was 2.70±0.18 at 1 month after switching to topiroxostat vs. 2.01±0.10 at 1 month after switching to febuxostat, and it was significantly higher while the patients were taking topiroxostat (P=0.002; Figure 3).
Change in estimated glomerular filtration rate (eGFR), urinary albumin, and oxidized low-density lipoprotein (O-LDL).
In the present cross-over study, we found that dose escalation was required significantly more often for topiroxostat than febuxostat over a 6-month treatment period (P=0.003), but there was no difference in s-UA between the 2 drugs after 6 months. Reduction of s-UA was more rapid with febuxostat than topiroxostat. O-LDL, a marker of oxidative stress, was significantly lower after 3 months of febuxostat treatment compared with topiroxostat treatment, but not after 6 months. Also, both drugs were largely similar with respect to their renoprotective, antioxidant, and anti-inflammatory effects at 6 months. It has been reported that febuxostat reduces UA more effectively than allopurinol,7 while the reduction of UA by topiroxostat and allopurinol is reported to be similar.8 In our previous study, febuxostat not only reduced UA more rapidly than allopurinol, but also achieved significantly lower s-Cr, eGFR, urinary albumin, cystatin-C, O-LDL, and hs-CRP compared with allopurinol.5,6 Given that the patient demographic profile differed between our previous study and the present study, head-to-head comparison is not appropriate. Like febuxostat, however, topiroxostat may also have a stronger renoprotective effect, greater antioxidant activity, and a stronger anti-inflammatory effect than allopurinol, suggesting that further investigation of this drug is warranted (Figure 4).
Change in international normalized ratio of prothrombin time (PT-INR).
Uric acid can damage the kidneys and an excessive increase of s-UA leads to a risk of CKD.9 Allopurinol reduces s-UA, thereby suppressing the progression of renal disease.10 According to clinical research on febuxostat, greater reduction of s-UA is associated with better maintenance of renal function.11
Urinary albumin is significantly reduced by topiroxostat compared with untreated patients.12 In a study comparing febuxostat and topiroxostat in mice, dose-dependent reduction of urinary albumin and plasma XOR by topiroxostat was noted, while febuxostat did not show dose-dependent activity. During treatment with topiroxostat, there was a significant correlation between the changes of urinary albumin and plasma XOR activity, suggesting that topiroxostat might reduce urinary albumin due to inhibition of plasma XOR activity.13 Our previous study of febuxostat vs. allopurinol demonstrated significant reduction of urinary albumin by febuxostat.5,6 In the present study, there was no statistical difference in the effect on urinary albumin between febuxostat and topiroxostat (3 months, P=0.369; 6 months, P=0.359). Accordingly, it seems that both topiroxostat and febuxostat reduce urinary albumin effectively in the clinical setting.
Fukui et al performed a clinical study in which allopurinol was switched to febuxostat, and they measured derivatives of reactive oxygen metabolites and the biological antioxidant potential as markers of oxidative stress. Both markers were significantly reduced after switching to febuxostat.14 In the present study, we measured O-LDL as an index of oxidative stress and found that it was significantly lower after 3 months of treatment with febuxostat vs. topiroxostat, but there was no difference after 6 months. In our previous comparative study of allopurinol and febuxostat, O-LDL was significantly lower in patients receiving febuxostat.5,6 There have been no reports on the influence of topiroxostat on oxidative stress. Given that subject demographics were different between our previous study and the present study, direct comparison of the results is not appropriate. It seems likely, however, that topiroxostat would be more effective at inhibiting oxidative stress than allopurinol, as would be expected due to reduction of oxidative stress by inhibiting XOR.
In the present study, warfarin activity was potentiated by ≥150% in 32% of patients receiving topiroxostat. Although there have been no previous reports about potentiation of the effect of warfarin by topiroxostat, the present finding suggests that this agent should be used with caution in patients on warfarin.
Febuxostat causes more marked and more rapid reduction of UA than topiroxostat. With regard to the antioxidant effect of these drugs, febuxostat was superior to topiroxostat after 3 months but no difference was observed after 6 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 cardiovascular disease.
Study LimitationsThis study was not conducted in treatment-naïve patients, and many of the subjects had previously shown a response to febuxostat. In addition, the sample size was fairly small. To confirm the present findings, a larger population of treatment-naïve patients with hyperuricemia should be investigated in a similar study in the future. The results should assist in elucidating the advantages and disadvantages of each medication.
The authors declare no conflict of interest.
A.S. received funding from Daiichi Sankyo and Teijin, and this study was also supported by a Research Grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology (No.21591805). A.S. has received lecture fees from Daiichi Sankyo. The other authors declare no conflict of interest.
