Aims To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. Methods and results This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat ( n = 537) and non-febuxostat groups ( n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively ( P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592–0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562–0.987; P = 0.041). Conclusion Febuxostat lowers uric acid and delays the progression of renal dysfunction. Registration ClinicalTrials.gov (NCT01984749).

This study is a prospective randomized open-label blinded endpoint study. Patient enrolment was started in November 2013 and was completed in October 2014. The patients will be followed for at least 3 years. The primary endpoint is a composite of cerebral, cardiovascular, and renal events, and all deaths including death due to cerebral, cardiovascular, and renal disease, new or recurring cerebrovascular disease, new or recurring non-fatal coronary artery disease, cardiac failure requiring hospitalization, arteriosclerotic disease requiring treatment, renal impairment, new atrial fibrillation, and all deaths other than cerebral or cardiovascular or renal disease. These events will be independently evaluated by the Event Assessment Committee under blinded information regarding the treatment group. The study was registered at ClinicalTrials.gov with the identifier NCT01984749.

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This multi-center prospective non-randomized comparative study investigated the effects of pitavastatin in patients with peripheral artery disease (PAD) in terms of exercise tolerance capacities and peripheral CD34+/133+ cell numbers. At baseline, a peripheral blood test was administered to 75 patients with PAD, along with a treadmill exercise test using the Skinner–Gardner protocol to measure asymptomatic walking distance (AWD) and maximum walking distance (MWD). Each patient was assigned to a 6-month pitavastatin treatment group (n = 53) or a control group (n = 22), according to the patient’s preference. The tests were repeated in both groups at 3 and 6 months. Baseline AWD and MWD correlated positively with the ankle-brachial pressure index (r = 0.342, p = 0.0032 and r = 0.324, p = 0.0054, respectively). Both AWD and MWD values improved at 3 and 6 months compared with baseline, and the degrees of their improvement were higher in the pitavastatin treatment group. CD34+/133+ cell numbers did not change over time or between groups. Eighty-seven percent of patients in the treatment group attained low-density lipoprotein cholesterol levels below 100 mg/dL after 3 months. The study shows that pitavastatin may be effective in increasing exercise tolerance capacity in patients with PAD.

Objectives Hyperuricaemia is recognised as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes are unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia. Methods This was a post hoc analysis of a randomised trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the end point (withdrawal or study completion) SUA levels and clinical outcomes. Primary end point was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events. Results In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% confidence interval: 1.05–3.87]), &gt;4 to ≤ 5 mg/dl (2.12 [1.07–4.20], &gt;6 to ≤ 7 mg/dl (2.42 [1.05–5.60]), and &gt;7 mg/dl (4.73 [2.13–10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels &gt;5 to ≤ 6 mg/dl (p= 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (p= 0.007 [Gray’s test]) and was not significant in the non-febuxostat treatment group (p= 0.212 [log-rank test]). Conclusion Optimal SUA levels by febuxostat treatment is 5–6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular, and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations. Trial Registration ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749