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Therapeutic strategy for efficient reduction of serum uric acid levels with allopurinol versus benzbromarone in hyperuricemic patients with essential hypertension — A randomized crossover study (terao study)
International Journal of Cardiology 224 (2016) 437–439
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Therapeutic strategy for efficient reduction of serum uric acid levels with allopurinol versus benzbromarone in hyperuricemic patients with essential hypertension — A randomized crossover study (terao study) Sunao Kojima a,⁎, Shinobu Kojima b, Atsuko Hifumi b, Hirofumi Soejima a, Hisao Ogawa c a b c
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Department of Internal Medicine, Terao Hospital, Kumamoto, Japan National Cerebral and Cardiovascular Center, Suita, Japan
a r t i c l e
i n f o
Article history: Received 21 August 2016 Accepted 20 September 2016 Available online 24 September 2016 Keywords: Xanthine oxidase inhibitor UACR Uric acid Hyperuricemia
Xanthine oxidase, an oxidative-stress-related enzyme, plays an important role in controlling endothelial function. Patients with elevated urine albumin/creatinine ratios (UACR) exhibit elevated cardiovascular risk, and hyperuricemia has been considered as a marker for future risk of cardiovascular disease [1,2]. Population studies have shown a reduction in the risk of non-fatal acute myocardial infarction in patients treated with allopurinol [3]. Doehner et al. [4] showed that allopurinol treatment in hyperuricemic patients with chronic heart failure improves endothelium-dependent vasodilation, with an inverse correlation between flow-dependent flow and urate levels. Although Doehner et al. did not find a similar effect in normouricemic subjects, George et al. demonstrated a clear dose/response curve and a definite effect on normouricemic subjects by using 300 mg/d and 600 mg/d doses of allopurinol, affirming the drug's effect on oxidative stress [5]. To compare the effects of different drugs used to treat hyperuricemia on cardiovascular risk factors, we designed a crossover study employing both a urate transporter-1 inhibitor (benzbromarone) and xanthine oxidase inhibitor (allopurinol). This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies. The study protocol was approved by the Human Ethics Review Committee of Kumamoto University and a signed consent form was obtained from each subject. ⁎ Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto City 8608556, Japan. E-mail address: [email protected] (S. Kojima).
http://dx.doi.org/10.1016/j.ijcard.2016.09.073 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
We randomized 14 consecutive patients with microalbuminuria having hypertension (N 140/90 mm Hg or taking anti-hypertensive medications) and hyperuricemia (serum uric acid levels N7 mg/dL) to receive either benzbromarone 25 mg once daily or allopurinol 200 mg twice daily for the first four weeks of the study (Table 1). Microalbuminuria was defined as an ACR of 30–300 mg/g of creatinine based on the analysis of morning urine. The patients stopped taking the drugs and went through a four-week washout period. During the third phase, which lasted for four weeks, the patients formerly taking benzbromarone were switched to allopurinol treatment, and the patients previously taking allopurinol were assigned to benzbromarone. Serum urate levels and UACR were evaluated in each phase. During this study period, the drugs administered, except for the study drugs, could not be changed. UACR in the morning urine samples was calculated as the urine albumin content divided by the urine creatinine content. Urinary urate-to-creatinine ratio (UUCR) was also calculated as the urine uric acid content divided by the urine creatinine content. All values were shown as mean ± standard deviation and categorical variables were expressed as numbers and percentages. Continuous variables that did not show a normal distribution were expressed as the median value (25th to 75th percentile range). A logistic regression analysis was performed to detect variables closely correlated with the reduction of UACR, including all clinical variables closely correlated with a change of UACR (P b 0.10). A P b 0.05 was defined as statistically significant. The analyses were performed using the JMP® Pro 12.2.0 (SAS Institute Inc., Cary, NC, USA). Benzbromarone 25 mg (pre-administration: 8.4 ± 1.1, postadministration: 4.8 ± 1.3 mg/dL, P b 0.0001) and allopurinol 200 mg (pre: 8.4 ± 1.0, post: 5.1 ± 0.9 mg/dL, P b 0.0001) could equally reduce the serum uric acid levels. There was a decline in UACR after the administration of benzbromarone or allopurinol; however, allopurinol (pre: 41.9 [31.0–71.4], post: 28.5 [16.9–40.8] mg/g creatinine, P = 0.0004) could significantly reduce the UACR levels compared to benzbromarone (pre: 39.6 [32.6–81.2], post: 53.0 [34.0–72.5] mg/g creatinine, P = 0.395). In patients receiving allopurinol, the change of UACR was positively correlated with a change of UUCR (r = 0.616, P = 0.019) (Fig. 1). The change of UACR was also correlated with a change of waist circumference (r = 0.526, P = 0.053), homeostasis model assessment for insulin resistance (r = 0.573, P = 0.032), and high-density lipoprotein cholesterol (r = − 0.485, P = 0.079). A multiple logistic
438
S. Kojima et al. / International Journal of Cardiology 224 (2016) 437–439
Table 1 The table describes the background of patients with microalbuminuria. The urine analysis values and the drugs administered are also given in the table. All values are shown as mean ± standard deviation and categorical variables are expressed as numbers and percentages. Continuous variables that did not show a normal distribution are expressed as the median value (25th to 75th percentile range). Patient background (n = 14) Age, y Men, n (%) Body mass index, kg/m2 Waist circumference, cm Hypertension, n (%) Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Diabetes mellitus, n (%) Fasting blood glucose, mg/dL Hemoglobin A1c, % Homeostasis model assessment for insulin resistance Homeostasis model assessment for beta cell function, % Hyperlipidemia, n (%) Low-density lipoprotein cholesterol, mg/dL High-density lipoprotein cholesterol, mg/dL Triglyceride, mg/dL Active smoking, n (%) Previous myocardial infarction, n (%) Serum creatinine, mg/dL Estimated glomerular filtration rate, mL/min/1.73 m2 Serum uric acid, mg/dL C-reactive protein, mg/dL Brain natriuretic peptide, pg/mL Urine pH Urate, mg/dL Creatinine, mg/dL Urate-to-creatinine ratio, % Albumin-to-creatinine ratio, mg/g· creatinine Drug administration Anti-thrombotic agents Nitrates β-blockers Calcium channel blockers Angiotensin converting enzyme inhibitors Angiotensin II receptor blockers Aldosterone antagonists Diuretics Statins
70 ± 13 10 (71) 25 ± 4 91 ± 11 14 (100) 116 ± 17 67 ± 10 0 (0) 105 ± 17 5.5 ± 0.2 1.7 (1.0–2.6) 54 (37–88) 11 (79) 107 ± 33 51 ± 16 125 ± 49 0 (0) 0 (0) 1.0 ± 0.2 55 ± 13 8.6 ± 1.1 0.05 (0.02–0.10) 83 (29–159) 5.6 (5.5–6.1) 46 (29–57) 91 (60–147) 48 (34–58) 45 (33–81) 8 (57) 1 (7) 6 (43) 8 (57) 4 (29) 7 (50) 1 (7) 4 (29) 7 (50)
assessment for insulin resistance (P = 0.009) and an increase of highdensity lipoprotein cholesterol (P = 0.002). Xanthine oxidase acts through two mechanisms, by the formation of urate and formation of free radicals. It has been shown that the mechanism underlying the effect of allopurinol on endothelial cells involves xanthine oxidase inhibition, and at higher doses, it most likely involves the inhibition of free radical formation. This has been demonstrated in patients with chronic heart failure and normal urate levels, by doseresponse comparison of the uricosuric drug, probenecid and the measurement of response to the drugs using forearm venous occlusion plethysmography [5]. Probenecid elicited no response, whereas allopurinol elicited a definite dose-related improvement in endothelial function. In an animal model of metabolic syndrome, allopurinol has been shown to reduce hypertension and proteinuria [6]. Xanthine oxidase activity was measured indirectly by urate [7], allantoin, [4] and UACR levels [2] and in large populations by the risk of myocardial infarction [3], all-cause mortality [8], and clinical outcomes in heart failure. Direct physiological measurements of xanthine oxidase activity include pulse wave velocity and left ventricular mass index [2], and venous occlusion plethysmography [4,5]. In the present study, the decrease of both serum uric acid levels and UUCR may be associated with the inhibition of xanthine oxidase; our study supports the use of UACR as a sensitive and non-invasive test for xanthine oxidase activity and target organ damage. Xanthine oxidase is a potential source of oxidative stress and may be an important therapeutic target. Xanthine oxidase inhibitors may be superior to urate transporter-1 inhibitors in reducing future cardiovascular events although both these inhibitors equally reduce the uric acid levels. However, Givertz et al. failed to demonstrate the clinical benefits of allopurinol in patients with reduced ejection fraction [9]. Further studies will be necessary owing to the increasing number of indications such as coronary artery disease for therapy with xanthine oxidase inhibitors. A prospective, randomized, open-label, blinded endpoint study to evaluate the preventive effects of febuxostat, a selective xanthine oxidase inhibitor, on cerebral, cardiovascular, and renal events in patients with hyperuricemia compared to the conventional treatment (FREED) is ongoing and similar results are expected [10]. Conflict of interest None declared.
regression analysis was performed to evaluate the clinical variables that can possibly have an impact on the reduction of UACR after allopurinol treatment. The results revealed that a decrease of UACR was closely associated with an increase of UUCR (P = 0.003), independent of a decrease of waist circumference (P = 0.003) and homeostasis model
Fig. 1. Positive correlation between the change of UACR and change of UUCR. UACR: urinary albumin-to-creatinine ratio. UUCR: urinary urate-to-creatinine ratio.
References [1] T. Sehestedt, J. Jeppesen, T.W. Hansen, S. Rasmussen, K. Wachtell, H. Ibsen, C. TorpPedersen, M.H. Olsen, Thresholds for pulse wave velocity, urine albumin creatinine ratio and left ventricular mass index using SCORE, Framingham and ESH/ESC risk charts, J. Hypertens. 30 (2012) 1928–1936. [2] S. Kojima, T. Sakamoto, M. Ishihara, K. Kimura, S. Miyazaki, M. Yamagishi, C. Tei, H. Hiraoka, M. Sonoda, K. Tsuchihashi, N. Shimoyama, T. Honda, Y. Ogata, K. Matsui, H. Ogawa, I. Japanese Acute Coronary Syndrome Study, Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese acute coronary syndrome study), Am. J. Cardiol. 96 (2005) 489–495. [3] F.J. de Abajo, M.J. Gil, A. Rodriguez, P. Garcia-Poza, A. Alvarez, V. Bryant, L.A. GarciaRodriguez, Allopurinol use and risk of non-fatal acute myocardial infarction, Heart 101 (2015) 679–685. [4] W. Doehner, N. Schoene, M. Rauchhaus, F. Leyva-Leon, D.V. Pavitt, D.A. Reaveley, G. Schuler, A.J. Coats, S.D. Anker, R. Hambrecht, Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies, Circulation 105 (2002) 2619–2624. [5] J. George, E. Carr, J. Davies, J.J. Belch, A. Struthers, High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid, Circulation 114 (2006) 2508–2516. [6] H.M. El-Bassossy, H.A. Shaltout, Allopurinol alleviates hypertension and proteinuria in high fructose, high salt and high fat induced model of metabolic syndrome, Transl. Res. 165 (2015) 621–630. [7] L.F. Loeffler, A. Navas-Acien, T.M. Brady, E.R. Miller 3rd, J.J. Fadrowski, Uric acid level and elevated blood pressure in US adolescents: national health and nutrition examination survey, 1999-2006, Hypertension 59 (2012) 811–817. [8] M. Dubreuil, Y. Zhu, Y. Zhang, J.D. Seeger, N. Lu, Y.H. Rho, H.K. Choi, Allopurinol initiation and all-cause mortality in the general population, Ann. Rheum. Dis. 74 (2015) 1368–1372.
S. Kojima et al. / International Journal of Cardiology 224 (2016) 437–439 [9] M.M. Givertz, K.J. Anstrom, M.M. Redfield, A. Deswal, H. Haddad, J. Butler, W.H. Tang, M.E. Dunlap, M.M. LeWinter, D.L. Mann, G.M. Felker, C.M. O'Connor, S.R. Goldsmith, E.O. Ofili, M.T. Saltzberg, K.B. Margulies, T.P. Cappola, M.A. Konstam, M.J. Semigran, S.E. McNulty, K.L. Lee, M.R. Shah, A.F. Hernandez, NHFCR network, effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) study, Circulation 131 (2015) 1763–1771.
439
[10] S. Kojima, K. Matsui, H. Ogawa, H. Jinnouchi, S. Hiramitsu, T. Hayashi, N. Yokota, N. Kawai, E. Tokutake, K. Uchiyama, M. Sugawara, H. Kakuda, Y. Wakasa, H. Mori, I. Hisatome, M. Waki, Y. Ohya, K. Kimura, Y. Saito, FJCC, on behalf of the febuxostat for cerebral and cardiorenovascular events prevention study (FREED) investigators, rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia, J. Cardiol. (2016) (in press).
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Therapeutic strategy for efficient reduction of serum uric acid levels with allopurinol versus benzbromarone in hyperuricemic patients with essential hypertension — A randomized crossover study (terao study) Sunao Kojima a,⁎, Shinobu Kojima b, Atsuko Hifumi b, Hirofumi Soejima a, Hisao Ogawa c a b c
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Department of Internal Medicine, Terao Hospital, Kumamoto, Japan National Cerebral and Cardiovascular Center, Suita, Japan
a r t i c l e
i n f o
Article history: Received 21 August 2016 Accepted 20 September 2016 Available online 24 September 2016 Keywords: Xanthine oxidase inhibitor UACR Uric acid Hyperuricemia
Xanthine oxidase, an oxidative-stress-related enzyme, plays an important role in controlling endothelial function. Patients with elevated urine albumin/creatinine ratios (UACR) exhibit elevated cardiovascular risk, and hyperuricemia has been considered as a marker for future risk of cardiovascular disease [1,2]. Population studies have shown a reduction in the risk of non-fatal acute myocardial infarction in patients treated with allopurinol [3]. Doehner et al. [4] showed that allopurinol treatment in hyperuricemic patients with chronic heart failure improves endothelium-dependent vasodilation, with an inverse correlation between flow-dependent flow and urate levels. Although Doehner et al. did not find a similar effect in normouricemic subjects, George et al. demonstrated a clear dose/response curve and a definite effect on normouricemic subjects by using 300 mg/d and 600 mg/d doses of allopurinol, affirming the drug's effect on oxidative stress [5]. To compare the effects of different drugs used to treat hyperuricemia on cardiovascular risk factors, we designed a crossover study employing both a urate transporter-1 inhibitor (benzbromarone) and xanthine oxidase inhibitor (allopurinol). This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies. The study protocol was approved by the Human Ethics Review Committee of Kumamoto University and a signed consent form was obtained from each subject. ⁎ Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto City 8608556, Japan. E-mail address: [email protected] (S. Kojima).
http://dx.doi.org/10.1016/j.ijcard.2016.09.073 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
We randomized 14 consecutive patients with microalbuminuria having hypertension (N 140/90 mm Hg or taking anti-hypertensive medications) and hyperuricemia (serum uric acid levels N7 mg/dL) to receive either benzbromarone 25 mg once daily or allopurinol 200 mg twice daily for the first four weeks of the study (Table 1). Microalbuminuria was defined as an ACR of 30–300 mg/g of creatinine based on the analysis of morning urine. The patients stopped taking the drugs and went through a four-week washout period. During the third phase, which lasted for four weeks, the patients formerly taking benzbromarone were switched to allopurinol treatment, and the patients previously taking allopurinol were assigned to benzbromarone. Serum urate levels and UACR were evaluated in each phase. During this study period, the drugs administered, except for the study drugs, could not be changed. UACR in the morning urine samples was calculated as the urine albumin content divided by the urine creatinine content. Urinary urate-to-creatinine ratio (UUCR) was also calculated as the urine uric acid content divided by the urine creatinine content. All values were shown as mean ± standard deviation and categorical variables were expressed as numbers and percentages. Continuous variables that did not show a normal distribution were expressed as the median value (25th to 75th percentile range). A logistic regression analysis was performed to detect variables closely correlated with the reduction of UACR, including all clinical variables closely correlated with a change of UACR (P b 0.10). A P b 0.05 was defined as statistically significant. The analyses were performed using the JMP® Pro 12.2.0 (SAS Institute Inc., Cary, NC, USA). Benzbromarone 25 mg (pre-administration: 8.4 ± 1.1, postadministration: 4.8 ± 1.3 mg/dL, P b 0.0001) and allopurinol 200 mg (pre: 8.4 ± 1.0, post: 5.1 ± 0.9 mg/dL, P b 0.0001) could equally reduce the serum uric acid levels. There was a decline in UACR after the administration of benzbromarone or allopurinol; however, allopurinol (pre: 41.9 [31.0–71.4], post: 28.5 [16.9–40.8] mg/g creatinine, P = 0.0004) could significantly reduce the UACR levels compared to benzbromarone (pre: 39.6 [32.6–81.2], post: 53.0 [34.0–72.5] mg/g creatinine, P = 0.395). In patients receiving allopurinol, the change of UACR was positively correlated with a change of UUCR (r = 0.616, P = 0.019) (Fig. 1). The change of UACR was also correlated with a change of waist circumference (r = 0.526, P = 0.053), homeostasis model assessment for insulin resistance (r = 0.573, P = 0.032), and high-density lipoprotein cholesterol (r = − 0.485, P = 0.079). A multiple logistic
438
S. Kojima et al. / International Journal of Cardiology 224 (2016) 437–439
Table 1 The table describes the background of patients with microalbuminuria. The urine analysis values and the drugs administered are also given in the table. All values are shown as mean ± standard deviation and categorical variables are expressed as numbers and percentages. Continuous variables that did not show a normal distribution are expressed as the median value (25th to 75th percentile range). Patient background (n = 14) Age, y Men, n (%) Body mass index, kg/m2 Waist circumference, cm Hypertension, n (%) Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Diabetes mellitus, n (%) Fasting blood glucose, mg/dL Hemoglobin A1c, % Homeostasis model assessment for insulin resistance Homeostasis model assessment for beta cell function, % Hyperlipidemia, n (%) Low-density lipoprotein cholesterol, mg/dL High-density lipoprotein cholesterol, mg/dL Triglyceride, mg/dL Active smoking, n (%) Previous myocardial infarction, n (%) Serum creatinine, mg/dL Estimated glomerular filtration rate, mL/min/1.73 m2 Serum uric acid, mg/dL C-reactive protein, mg/dL Brain natriuretic peptide, pg/mL Urine pH Urate, mg/dL Creatinine, mg/dL Urate-to-creatinine ratio, % Albumin-to-creatinine ratio, mg/g· creatinine Drug administration Anti-thrombotic agents Nitrates β-blockers Calcium channel blockers Angiotensin converting enzyme inhibitors Angiotensin II receptor blockers Aldosterone antagonists Diuretics Statins
70 ± 13 10 (71) 25 ± 4 91 ± 11 14 (100) 116 ± 17 67 ± 10 0 (0) 105 ± 17 5.5 ± 0.2 1.7 (1.0–2.6) 54 (37–88) 11 (79) 107 ± 33 51 ± 16 125 ± 49 0 (0) 0 (0) 1.0 ± 0.2 55 ± 13 8.6 ± 1.1 0.05 (0.02–0.10) 83 (29–159) 5.6 (5.5–6.1) 46 (29–57) 91 (60–147) 48 (34–58) 45 (33–81) 8 (57) 1 (7) 6 (43) 8 (57) 4 (29) 7 (50) 1 (7) 4 (29) 7 (50)
assessment for insulin resistance (P = 0.009) and an increase of highdensity lipoprotein cholesterol (P = 0.002). Xanthine oxidase acts through two mechanisms, by the formation of urate and formation of free radicals. It has been shown that the mechanism underlying the effect of allopurinol on endothelial cells involves xanthine oxidase inhibition, and at higher doses, it most likely involves the inhibition of free radical formation. This has been demonstrated in patients with chronic heart failure and normal urate levels, by doseresponse comparison of the uricosuric drug, probenecid and the measurement of response to the drugs using forearm venous occlusion plethysmography [5]. Probenecid elicited no response, whereas allopurinol elicited a definite dose-related improvement in endothelial function. In an animal model of metabolic syndrome, allopurinol has been shown to reduce hypertension and proteinuria [6]. Xanthine oxidase activity was measured indirectly by urate [7], allantoin, [4] and UACR levels [2] and in large populations by the risk of myocardial infarction [3], all-cause mortality [8], and clinical outcomes in heart failure. Direct physiological measurements of xanthine oxidase activity include pulse wave velocity and left ventricular mass index [2], and venous occlusion plethysmography [4,5]. In the present study, the decrease of both serum uric acid levels and UUCR may be associated with the inhibition of xanthine oxidase; our study supports the use of UACR as a sensitive and non-invasive test for xanthine oxidase activity and target organ damage. Xanthine oxidase is a potential source of oxidative stress and may be an important therapeutic target. Xanthine oxidase inhibitors may be superior to urate transporter-1 inhibitors in reducing future cardiovascular events although both these inhibitors equally reduce the uric acid levels. However, Givertz et al. failed to demonstrate the clinical benefits of allopurinol in patients with reduced ejection fraction [9]. Further studies will be necessary owing to the increasing number of indications such as coronary artery disease for therapy with xanthine oxidase inhibitors. A prospective, randomized, open-label, blinded endpoint study to evaluate the preventive effects of febuxostat, a selective xanthine oxidase inhibitor, on cerebral, cardiovascular, and renal events in patients with hyperuricemia compared to the conventional treatment (FREED) is ongoing and similar results are expected [10]. Conflict of interest None declared.
regression analysis was performed to evaluate the clinical variables that can possibly have an impact on the reduction of UACR after allopurinol treatment. The results revealed that a decrease of UACR was closely associated with an increase of UUCR (P = 0.003), independent of a decrease of waist circumference (P = 0.003) and homeostasis model
Fig. 1. Positive correlation between the change of UACR and change of UUCR. UACR: urinary albumin-to-creatinine ratio. UUCR: urinary urate-to-creatinine ratio.
References [1] T. Sehestedt, J. Jeppesen, T.W. Hansen, S. Rasmussen, K. Wachtell, H. Ibsen, C. TorpPedersen, M.H. Olsen, Thresholds for pulse wave velocity, urine albumin creatinine ratio and left ventricular mass index using SCORE, Framingham and ESH/ESC risk charts, J. Hypertens. 30 (2012) 1928–1936. [2] S. Kojima, T. Sakamoto, M. Ishihara, K. Kimura, S. Miyazaki, M. Yamagishi, C. Tei, H. Hiraoka, M. Sonoda, K. Tsuchihashi, N. Shimoyama, T. Honda, Y. Ogata, K. Matsui, H. Ogawa, I. Japanese Acute Coronary Syndrome Study, Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese acute coronary syndrome study), Am. J. Cardiol. 96 (2005) 489–495. [3] F.J. de Abajo, M.J. Gil, A. Rodriguez, P. Garcia-Poza, A. Alvarez, V. Bryant, L.A. GarciaRodriguez, Allopurinol use and risk of non-fatal acute myocardial infarction, Heart 101 (2015) 679–685. [4] W. Doehner, N. Schoene, M. Rauchhaus, F. Leyva-Leon, D.V. Pavitt, D.A. Reaveley, G. Schuler, A.J. Coats, S.D. Anker, R. Hambrecht, Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies, Circulation 105 (2002) 2619–2624. [5] J. George, E. Carr, J. Davies, J.J. Belch, A. Struthers, High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid, Circulation 114 (2006) 2508–2516. [6] H.M. El-Bassossy, H.A. Shaltout, Allopurinol alleviates hypertension and proteinuria in high fructose, high salt and high fat induced model of metabolic syndrome, Transl. Res. 165 (2015) 621–630. [7] L.F. Loeffler, A. Navas-Acien, T.M. Brady, E.R. Miller 3rd, J.J. Fadrowski, Uric acid level and elevated blood pressure in US adolescents: national health and nutrition examination survey, 1999-2006, Hypertension 59 (2012) 811–817. [8] M. Dubreuil, Y. Zhu, Y. Zhang, J.D. Seeger, N. Lu, Y.H. Rho, H.K. Choi, Allopurinol initiation and all-cause mortality in the general population, Ann. Rheum. Dis. 74 (2015) 1368–1372.
S. Kojima et al. / International Journal of Cardiology 224 (2016) 437–439 [9] M.M. Givertz, K.J. Anstrom, M.M. Redfield, A. Deswal, H. Haddad, J. Butler, W.H. Tang, M.E. Dunlap, M.M. LeWinter, D.L. Mann, G.M. Felker, C.M. O'Connor, S.R. Goldsmith, E.O. Ofili, M.T. Saltzberg, K.B. Margulies, T.P. Cappola, M.A. Konstam, M.J. Semigran, S.E. McNulty, K.L. Lee, M.R. Shah, A.F. Hernandez, NHFCR network, effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) study, Circulation 131 (2015) 1763–1771.
439
[10] S. Kojima, K. Matsui, H. Ogawa, H. Jinnouchi, S. Hiramitsu, T. Hayashi, N. Yokota, N. Kawai, E. Tokutake, K. Uchiyama, M. Sugawara, H. Kakuda, Y. Wakasa, H. Mori, I. Hisatome, M. Waki, Y. Ohya, K. Kimura, Y. Saito, FJCC, on behalf of the febuxostat for cerebral and cardiorenovascular events prevention study (FREED) investigators, rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia, J. Cardiol. (2016) (in press).