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Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP)

Franse, Lonneke V.1,6; Pahor, Marco2; Bari, Mauro Di3; Shorr, Ronald I.4; Wan, Jim Y.4; Somes, Grant W.4; Applegate, William B.5

Original articles

Objective To assess longitudinally the association of serum uric acid and its change due to diuretic treatment with cardiovascular events in hypertensive patients.

Design Cohort study in a randomized trial.

Setting Cohort of hypertensive patients.

Participants A total of 4327 men and women, aged ≥ 60 years, with isolated systolic hypertension, randomized to placebo or chlorthalidone, with the addition of atenolol or reserpine if needed, were observed for 5 years.

Main outcome measures Major cardiovascular events, coronary events, stroke and all-cause mortality.

Results Cardiovascular event rates for quartiles of baseline serum uric acid were: I, 32.7 per 1000 person-years; II, 34.5 per 1000 person-years; III, 38.1 per 1000 person-years; and IV, 41.4 per 1000 person-years (P for trend = 0.02). The adjusted hazard ratio (HR), of cardiovascular events for the highest quartile of serum uric acid versus the lowest quartile was 1.32 (95% CI, 1.03–1.69). The benefit of active treatment was not affected by baseline serum uric acid. After randomization, an increase of serum uric acid < 0.06 mmol/l (median change) in the active treatment group was associated with a HR of 0.58 (0.37–0.92) for coronary events compared with those with a serum uric acid increase ≥ 0.06 mmol/l. This difference was not explained by blood pressure effects. Those with a serum uric acid increase ≥ 0.06 mmol/l in the active treatment group had a similar risk of coronary events as the placebo group.

Conclusions Serum uric acid independently predicts cardiovascular events in older persons with isolated systolic hypertension. Monitoring serum uric acid change during diuretic treatment may help to identify patients who will most benefit from treatment.

1Institute for Research in Extramural Medicine, Vrije Universiteit, Amsterdam, The Netherlands

2Sticht Center on Aging, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA

3Department of Gerontology and Geriatrics, University of Florence and ‘Careggi’ Hospital, Florence, Italy

4Department of Preventive Medicine, University of Tennessee, Memphis, Tennessee, USA

5Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

6Correspondence and requests for reprints to Dr Lonneke Franse, MPH, Institute for Research in Extramural Medicine, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Tel: + 31 20 4448177; fax: + 31 20 4448361; e-mail:

Sponsorship: The Systolic Hypertension in the Elderly Program (SHEP) was supported by contracts with the National Heart, Lung, and Blood Institute and the National Institute on Aging. Drugs were supplied by the Lemmon Co (Sellersville, Pennsylvania, USA), Wyeth Laboratories/Ayerst Laboratories, AH Robins Co (Richmond, Virginia, USA), and Stuart Pharmaceuticals (Wilmington, Delaware, USA). The present analysis was funded by a research grant from Merck (Whitehouse Station, New Jersey, USA).

Potential conflict of interest: Dr Pahor has received research grants from BMS and Merck, and has received fees for giving talks at meetings sponsored by BMS, Merck, Parke Davis, Boehringer Ingelheim and Bayer.

Received 22 December 1999 Revised 28 March 2000 Accepted 15 April 2000

© 2000 Lippincott Williams & Wilkins, Inc.