Class effect of xanthine oxidase inhibitors on flow‐mediated dilatation in hypertensive patients: A randomized controlled trial

Abstract

A direct comparison of the effects of febuxostat and allopurinol on flow‐mediated dilatation (FMD) will help to clarify which agent provides a better reduction of cardiovascular risk in hypertensive patients. Hypertensive patients with hyperuricemia were randomized into a febuxostat (10‐40 mg, n = 33) or allopurinol (100‐200 mg, n = 31) group and followed up for 6 months. Both the febuxostat (7.9 ± 1.3 mg/dL vs 5.6 ± 1.0 mg/dL, P < .001) and allopurinol (8.2 ± 1.3 mg/dL vs 6.1 ± 1.0 mg/dL, P < .001) groups exhibited significant reductions in uric acid after treatment. There was no significant difference in the change in FMD between the two treatment groups (0.6 ± 2.6% vs 0.2 ± 2.3%, P = .504). However, stratified analysis showed that febuxostat achieved a significantly greater change in FMD compared to allopurinol in the elderly group (1.3 ± 2.9% vs −0.7%±1.8%, P = .047). There was no difference in the improvement of FMD between febuxostat and allopurinol, but febuxostat may provide an improvement of FMD in elderly people.

1. INTRODUCTION

Several previous studies reported that hyperuricemia was associated with a risk of cardiovascular events in hypertensive patients.1, 2 Xanthine oxidase inhibitors (XOIs) are first‐line drugs for the treatment of hyperuricemia. Febuxostat is a novel potent non‐purine selective XOI that inhibits both the oxidized and reduced forms of xanthine oxidase and decreases the formation of uric acid.3, 4

Several recent studies have examined whether febuxostat therapy can mitigate kidney dysfunction and reduce risk of heart failure in the general clinical population.5, 6 Against the background of those previous studies showing an effect of febuxostat, the findings of the CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial demonstrated that febuxostat was not inferior to allopurinol in terms of adverse cardiovascular events, whereas the risks of all‐cause mortality and cardiovascular mortality were higher by febuxostat than allopurinol administration in patients with gout.7

Hypertension is associated with endothelial dysfunction.8 Flow‐mediated dilatation (FMD) has been widely used for the assessment of endothelial function.9, 10, 11 The high activity of xanthine oxidase, which is closely linked to hyperuricemia, has been recognized as an important source of radical oxygen species, which per se can deteriorate vascular function and, in turn, results in a risk of cardiovascular events.12 A direct comparison of the effects of febuxostat and allopurinol on FMD will allow us to better understand whether febuxostat provides a greater benefit in terms of reducing cardiovascular risk compared with allopurinol in the hypertensive population. We conducted a randomized controlled study to test the hypothesis that febuxostat is superior to allopurinol for the improvement of FMD in hypertensive patients with hyperuricemia.

2. METHODS

2.1. Study subjects

The study participants were recruited from the outpatients of two institutes, the International University of Health and Welfare Hospital (Nasushiobara, Japan) and Jichi Medical University Hospital (Shimotsuke, Japan). The entry period was from October 2015 to April 2018. Initially, we consecutively enrolled patients aged ≥20 years with hypertension (a history of antihypertensive treatment or office systolic blood pressure [BP] ≥140 mm Hg or office diastolic BP ≥90 mm Hg) who had already been treated for hyperuricemia or high uric acid (≥8.0 mg/dL) and agreed to participate in this study. During the 2‐week run‐in period, patients who were already being treated with anti‐hyperuricemia drugs were instructed to stop those drugs. Patients were excluded if they currently had gout attack, renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73m²), and/or hepatic dysfunction. The study protocol was reviewed and approved by the institutional review boards of the participating study sites. All patients provided written informed consent to participate in the study.

2.2. Study design

The present study was a multicentered, prospective, randomized, open‐label clinical study with two treatment arms. The primary objective of the study was to evaluate the efficacy of a 6‐month treatment with febuxostat in terms of FMD improvement in comparison with allopurinol. The change in brachial‐ankle pulse wave velocity (baPWV) and urinary albumin creatinine ratio (UACR) were prespecified as secondary endpoints. The flow diagram of this study is illustrated in Figure 1. Eligible patients were randomized to initially receive either febuxostat (10 mg) or allopurinol (100 mg) followed by titration to 40 mg febuxostat or 200 mg allopurinol, respectively. In patients whose uric acid levels became less than 6.0 mg/dL, the titrations were stopped. Other drugs that had the potential to interfere with the safety and efficacy of the study medications were also not allowed. At the baseline and the end of the study, FMD, baPWV, UACR and office BP were measured, and blood and urine tests were performed. The study was registered with the University Hospital Medical Information Network (study ID: UMIN000019530).

Figure 1.

Flow diagram of the study

2.3. FMD

Flow‐mediated dilatation was measured by a system equipped with a 10‐MHz linear array transducer and a novel stereotactic probe‐holding device (UNEX EF 18G; UNEX). This system had already been validated in a previous study.9 Briefly, after baseline images of the brachial artery were recorded, occlusion of the forearm blood flow was provoked and maintained for a period of 5 minutes by a cuff inflated to 50 mm Hg above the participant's systolic BP. Images of the brachial artery were recorded for 2 minutes after cuff deflation. The diameter of the brachial artery per beat was synchronized with the electrocardiographic R‐wave and was tracked automatically by the automated edge detection system included with the FMD device. The FMD was defined as the percentage change in the maximum diameter from the resting baseline diameter. Participants were instructed to rest over 15 minutes in the supine position and the fasting state (ie, after a 12‐hour fast including cessation of all medications) before the measurement of FMD.

2.4. baPWV and UACR

Office BP was measured by physicians or nurses using an upper arm cuff validated oscillometric BP device. The baPWV was measured with a volume‐plethysmographic device (form/BP‐203RPE II; Omron Healthcare). The details of the measurements and the reproducibility of this automatic method have been described in previous reports. The means of the right and left baPWV values were used for the analysis. Blood and spot urine samples were collected in the morning in a fasting state. The UACR was measured using an immunoturbidity kit (AutoWako Microalbumin; Wako Pure Chemical Industries).

2.5. Other clinical assessments

Diabetes mellitus was defined as a self‐reported history of a physician's diagnosis, diabetes mellitus medication use, fasting blood glucose level ≥126 mg/dL, or non‐fasting glucose level ≥200 mg/dL; dyslipidemia was defined as a total cholesterol level of ≥240 mg/dL or treated hyperlipidemia; and chronic kidney disease (CKD) was defined as the presence of proteinuria or an estimated glomerular filtration rate of <60 mL/min/1.73m².

2.6. Statistical analysis

The study was designed to include 60 patients (30 in each group) in order that it would have 80% power (2‐sided) at the 5% α‐level to detect a 1.5% difference in FMD between patients taking the two agents. Assumptions included an estimated SD (standard deviation) in change in FMD of 2%.

All of the data were expressed as the mean ± SD or as a percentage. As the distributions of UACR were highly skewed, UACR was expressed as the median value [interquartile range: IQR], and log‐transformed before statistical analysis. Differences between the groups at baseline were analyzed using the unpaired t test for continuous variables or the chi‐square test for categorical variables. We also stratified analyses according to participants’ characteristics (aged <65 years vs ≥65 years; body mass index [BMI] <25 kg/m² vs ≥25 kg/m²; the presence of CKD or not; the presence of diabetes or not). Two‐sided values of P < .05 were considered to indicate statistical significance. All of the statistical analyses were performed with STATA version 12.1 (STATACorp).

3. RESULTS

3.1. Baseline characteristics

A total of 66 patients were randomly allocated to the febuxostat (33 patients) or allopurinol (33 patients) group. Two patients voluntarily withdrew from the study during the treatment period (Figure 1), leaving a final group of 64 patients who completed the study (59 men and 5 women; mean age, 60.8 years). There were no adverse events during the treatment period in either group.

There were no significant differences in the baseline demographic and clinical characteristics of patients between the febuxostat and allopurinol groups (Table 1). Hypertension was a comorbidity in both groups (96.9%). Most patients were taking a calcium antagonist for hypertensive treatment (93.9%).

Table 1.

Baseline characteristics of the study patients

	Febuxostat	Allopurinol	P value
Number	33	31
Age, years	60.6 ± 12.0	61.1 ± 9.2	.873
Male, %	87.9	96.8	.185
Body mass index, kg/m2	26.8 ± 3.1	27.2 ± 3.8	.639
Smoking, %	9.1	12.9	.678
Alcohol, %	63.6	61.3	.629
Cardiovascular comorbidities
Diabetes, %	18.2	29.0	.306
Dyslipidemia, %	36.4	58.1	.082
Stroke, %	0.0	3.2	.298
Myocardial infarction, %	3.1	0.0	.321
Heart failure, %	0.0	3.2	.298
Medication
Calcium antagonist, %	97.0	90.3	.272
ARB, %	75.8	64.5	.325
ACEi, %	6.1	3.2	.592
Beta‐blocker, %	24.2	35.5	.325
Diuretics, %	51.5	41.9	.443
Statin, %	29.0	41.9	.288
Anti‐diabetic drug, %	16.1	20.0	.694
Office SBP, mm Hg	133 ± 12	131 ± 8.9	.504
Office DBP, mm Hg	76 ± 13	79 ± 7.7	.362
Office PR, bpm	68 ± 12	68 ± 10	.785
Uric acid, mg/dL	7.9 ± 1.3	8.2 ± 1.3	.278
FMD, %	5.2 ± 1.7	5.8 ± 2.0	.228
UACR, mg/g⋅crea	9.3 [5.9, 18.2]	8.9 [4.2. 27.0]	.407
baPWV, cm/sb	1559 ± 266	1479 ± 251	.223

Data are mean ± SD, median [IQR] or percentage.

Abbreviations: ACEi, angiotensin‐converting enzyme inhibitor; ARB, indicates angiotensin II receptor blocker; baPWV, brachial‐ankle pulse wave velocity; DBP, diastolic blood pressure; FMD, flow‐mediated dilatation; PR, pulse rate; SBP, systolic blood pressure; UACR, urinary albumin creatinine ratio.

^aNumbers of subjects were 29 and 27 in the febuxostat and allopurinol group, respectively.

^bThe number of subjects was 32 in the febuxostat group.

3.2. Primary endpoint

The average doses of febuxostat and allopurinol at follow‐up were 20 ± 8.7 mg and 161 ± 49 mg, respectively. Concerning the change in uric acid, both the febuxostat (7.9 ± 1.3 mg/dL vs 5.6 ± 1.0 mg/dL, P < .001) and allopurinol (8.2 ± 1.3 mg/dL vs 6.1 ± 1.0 mg/dL, P < .001) groups exhibited significant reductions by treatment. The change in uric acid was not significantly different between the two groups (−2.2 ± 1.0 mg/dL vs −2.2 ± 1.4 mg/dL, P = .754). FMD at baseline was also not significantly different between the febuxostat and allopurinol group (Table 1). In both groups, although FMD was not reduced, the change in FMD was not significantly different between the two groups (Figure 2). Stratified analysis showed that febuxostat treatment achieved a significantly greater improvement in FMD compared to allopurinol treatment in the elderly group (1.3 ± 2.9% vs −0.7%±1.8%, P = .047, Table S1).

Figure 2.

Change in flow‐mediated dilatation between baseline and follow‐up in the febuxostat and allopurinol group

3.3. Secondary endpoint

The numbers of patients in whom UACR and baPWV were measured at both baseline and follow‐up in the febuxostat group were 29 and 32, respectively, and the corresponding numbers in the allopurinol group were 21 and 32, respectively. There was no significant difference in UACR and baPWV at baseline between the two groups. In addition, there was no significant difference in change in UACR and baPWV between the two groups (Table 2). Sub‐group analysis stratified by age, BMI, and the presence of CKD and diabetes did not reveal any significant difference in the change in UACR or baPWV between the two groups (Table S1).

Table 2.

Changes in UACR and PWV

	Febuxostat	Allopurinol	P value
Log UACR, mg/g⋅cre
Number	29	27
Baseline	1.19 ± 0.75	1.05 ± 0.47	.407
Follow‐up	1.24 ± 0.83	1.05 ± 0.55	.320
Change	0.06 ± 0.34	0.01 ± 0.31	.578
baPWV, cm/s
Number	32	31
Baseline	1559 ± 266	1479 ± 251	.223
Follow‐up	1541 ± 249	1498 ± 233	.483
Change	−18 ± 178	19 ± 118	.333

Abbreviations: baPWV, brachial‐ankle pulse wave velocity; UACR, indicates urinary albumin creatinine ratio.

4. DISCUSSION

In this study, the change in FMD as a primary endpoint was not significantly different between patients treated with febuxostat and those treated with allopurinol. However, sub‐group analysis showed that febuxostat provided a greater improvement of FMD compared with allopurinol in elderly subjects. Concerning the change in UACR and baPWV, there was no significant difference between our two treatment groups of hypertensive patients with hyperurecimia.

To the best of our knowledge, this is the first randomized controlled trial to compare FMD as an index of endothelial function between patients treated with febuxostat and allopurinol. Because febuxostat was recently developed for the treatment of hyperuricemia,3 there have been only a few reports about the ability of this agent to improve endothelial function. In a rat model, a previous study demonstrated that a therapeutic dose of febuxostat appropriate for hyperuricemia considerably improved endothelial dysfunction.13 Alshahawey et al14 randomized 57 hemodialysis patients into a febuxostat treatment group and control group and followed them over two months. They concluded that febuxostat improved endothelial dysfunction, but they used asymmetric dimethylarginine as the index of endothelial dysfunction. Concerning allopurinol, a meta‐analysis of 10 randomized controlled trials demonstrated that subjects treated with allopurinol exhibited a significantly greater improvement in FMD compared with controls.15 In the current study, there was no significant difference in the change in FMD by treatment between the febuxostat and allopurinol group. The majority of subjects in this study had already been treated with drugs to reduce the risk of cardiovascular events, such as antihypertensive drugs, diabetes drugs, and statins, all of which would influence FMD. Therefore, adding an XOI to these therapeutic regimens may not have yielded a greater improvement of FMD.

In our elderly hypertensive subjects, febuxostat provided a greater improvement of FMD compared with allopurinol. Sezai et al16 reported that treatment with febuxostat decreased the oxidized low‐density lipoprotein (LDL) level more than allopurinol in high‐risk cardiac surgery patients with hyperuricemia. Oxidized LDL is used as an index of oxidative stress, and its increase has been associated with enhancement of endothelial injury and thereby progression of atherosclerosis.17 Oxidized inhibition of febuxostat to improve endothelial function may be effective in high‐risk patients, but further study will be needed to confirm this.

In this study, there were no significant differences in the change in UACR or baPWV between febuxostat and allopurinol treatment. Because these outcomes were secondary endpoints, they had limited power. Several previous studies compared the effects on baPWV between febuxostat and allopurinol treatment, but their results were inconsistent.16, 18 Tausche et al18 reported that 1 year of allopurinol treatment increased carotid‐femoral PWV in patients with gout, while 1 year of febuxostat treatment did not; however, the number of subjects examined in their study was very small. Sezai et al16 reported that there was no significant difference in PWV reduction between febuxostat and allopurinol treatment in high‐risk cardiac surgery patients with hyperuricemia. We expected that there may be difference in the change in UACR between febuxostat and allopurinol treatment, because UACR has been linked to a systematic endothelial disorder due to an elevation of glomerular and vascular oxidase stress.19 For example, an intervention consisting of anti‐oxidant therapy using statin, vitamin E, and homocysteine‐lowering therapy during 2 years reduced UACR and increased FMD.20

There were several limitations in this study. The number of subjects was relatively small. Therefore, the statistical power was not sufficient to interpret the results of the sub‐analysis. In addition, the findings of this study may not be generalized to any other population.

In conclusion, there was no significant difference in the improvement of FMD between febuxostat and allopurinol treatment in hypertensive outpatients who had already been treated for hyperuricemia or high uric acid. In elderly patients, febuxostat might provide a greater improvement of FMD compared with allopurinol.

CONFLICTS OF INTERESTS

Kario K has received research grants from Sanwa Kagaku Kenkyusho Co., Sumitomo Dainippon Pharma Co., Takeda Pharmaceutical Co. and Pfizer Japan Inc. Kabutoya T has received a research grant from Tanabe Mitsubishi Pharma Corporation. All other authors have no conflicts of interest to declare.

AUTHOR CONTRIBUTIONS

KK supervised the conduct of the study and had the primary responsibility of writing this paper. SH conducted data analysis and wrote the Introduction, Methods, Results, and Discussion sections. KK reviewed/edited the manuscript and contributed to the Discussion section. TK and HU collected the data.

Supporting information

 

Hoshide S, Kabutoya T, Ueno H, Kario K. Class effect of xanthine oxidase inhibitors on flow‐mediated dilatation in hypertensive patients: A randomized controlled trial. J Clin Hypertens. 2020;22:451–456. 10.1111/jch.13757