Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion - - PowerPoint PPT Presentation

Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED)

Sunao Kojima, Kunihiko Matsui, Shinya Hiramitsu, Ichiro Hisatome, Masako Waki, Kazuaki Uchiyama, Naoto Yokota, Eiichi Tokutake, Yutaka Wakasa, Hideaki Jinnouchi, Hirokazu Kakuda, Takahiro Hayashi, Naoki Kawai, Hisao Mori, Masahiro Sugawara, Yusuke Ohya, Kazuo Kimura, Yoshihiko Saito, Hisao Ogawa on behalf of the Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED) investigators

Conclusion

 Uric acid level lowering by febuxostat provides clinical benefit

for prevention of cerebral, cardiovascular, and renal events in elderly patients with hyperuricemia.

 Febuxostat may be expected to prevent the development and

progression of chronic kidney disease.

Background -1-

 Urate-lowering therapy with anti-hyperuricemic drugs can prevent the

recurrence of urate deposition–related diseases.

(Perez-Ruiz F et al. Arthritis Rheum 2002)

 Hyperuricemia may contribute to the development and progression of

cerebrocardiovascular diseases and mortality.

(Kojima S, et al. Am J Cardiol 2005)

(Li M, et al. Sci Rep 2016)

 Febuxostat approved in 2011 in Japan has a more potent serum uric acid–

lowering effect compared with that of allopurinol.

(Kamatani N, et al. J Clin Rheumatol 2011)

Production and Metabolism of Uric Acid

Adenosine Inosine Hypoxanthine Xanthine

Uric acid (UA)

O2

• ・

Xanthine

• xidoreductase

Allopurinol

Oxypurinol + +

Excretion Allantoin

Urate

• xidase

Renal (2/3) Gastrointestinal (1/3) O2

• ・

Human Vascular Smooth Muscle Cells

Nature 2002;417:447-452 Circulation 2003;107:1951-1953 J Am Soc Nephrol 2006;17:1791-1795

Na+ anion－

UA

URAT 1

Benzbromarone probenecid

Febuxostat

 The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with

Gout and Cardiovascular Morbidities (CARES) trial revealed that all-cause mortality and cardiovascular mortality were higher with febuxostat treatment than with allopurinol treatment in gout patients with cardiovascular disease.

(White WB, et al. N Engl J Med 2018)

 It remains to be elucidated whether the mortality results of the CARES trial

are due to beneficial effects of allopurinol or deleterious effects of febuxostat.

(Choi H, et al. Arthritis Rheumatol 2018)

Background -2-

Aim

 The Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) was conducted to compare the

• ccurrence of cerebral, cardiovascular, and renal events in

elderly patients with hyperuricemia at risk for cerebral or cardiorenovascular disease treated with febuxostat and those treated with conventional therapy.

Design

• Multicenter, prospective, randomized open-label, blinded end point

(PROBE), two-arm parallel treatment groups study

 Subjects

• Elderly patients aged 65 years or older with hyperuricemia (serum uric

acid level >7.0 to ≤9.0 mg/dL) who had one or more risks for cerebral, cardiovascular, or renal disease

• a. History of active hypertension
• b. History of active type 2 diabetes mellitus
• c. Renal disorder (eGFR ≥30 to <60 mL/min/1.73 m2) within 3 months

prior to enrollment

• d. History of cerebrocardiovascular disease occurring >3 months prior to

enrollment

(Kojima S, et al. J Cardiol 2017;69:169-75)

Methods

Non-febuxostat group Consider use of allopurinol 100 mg if serum uric acid is elevated Informed consent Screening Enrollment Randomization

40 mg 20 mg 10 mg W0 W4 W8 W12 M6 M36 (Investigation every 6 months)

Study treatment continued up to Month 36

Febuxostat group Administer febuxostat

Lifestyle modification for management of hyperuricemia in all patients

(Kojima S, et al. J Cardiol 2017;69:169-75)

Methods

Changes in serum uric acid level

Time point of blood sample collection 2 4 6 8 10 12 Serum uric acid (mg/dL)

* * * * * * * * *

Febuxostat group Non-febuxostat group mean±SD

*P<0.001

Febuxostat: 4.50±1.52 mg/dL Non-febuxostat: 6.76±1.45 mg/dL

Results

Primary End Point

(Composite of death due to any cause, cerebrovascular disease, non-fatal coronary artery disease, heart failure requiring hospitalization, arteriosclerotic disease requiring treatment, renal impairment, atrial fibrillation)

0.1 0.2 0.3 0.4

Febuxostat group (n=537) Non-febuxostat group (n=533)

Cumulative rate of the primary endpoint Hazard ratio=0.750 (95% CI, 0.592-0.950, P=0.017) 3 6 9 12 15 18 21 24 27 30 33 36

537 515 473 429 399 372 209 533 501 451 391 370 341 188

Months

• No. at risk

Febuxostat Non-febuxostat

23.3% 28.7%

Secondary End Point

Febuxostat group (n=537) Non-febuxostat group (n=533) Hazard ratio (95% confidence interval) P value Death due to cerebral, cardiovascular and renal disease 6 (1.1) 6 (1.1) 0.958 (0.314-2.926) 0.940 Cerebrovascular disease 9 (1.7) 7 (1.3) 1.271 (0.479-3.371) 0.630 Non-fatal coronary artery disease 4 (0.7) 7 (1.3) 0.559 (0.167-1.869) 0.345 Heart failure requiring hospitalization 9 (1.7) 12 (2.3) 0.699 (0.290-1.689) 0.427 Arteriosclerotic disease requiring treatment 2 (0.4) 3 (0.6) 0.644 (0.107-3.873) 0.631 Renal impairment 87 (16.2) 109 (20.5) 0.745 (0.562-0.987) 0.041 Atrial fibrillation 4 (0.7) 3 (0.6) 1.320 (0.292-5.968) 0.719 Death due to other cause 4 (0.7) 6 (1.1) 0.635 (0.179-2.253) 0.482 Hard end point (composite of death due to any cause, cerebrovascular disease, or non- fatal coronary artery disease) 23 (4.3) 26 (4.9) 0.861 (0.492-1.506) 0.600

Key messages

• Febuxostat has greater renoprotective effect. However,

cardiovascular protection may not be expected compared with renal protection.

• Based on the results of both the CARES trial and our present

study, treatment with febuxostat did not reduce major cerebrocardiovascular events.