Original investigations
Pathogenesis and treatment of kidney disease and hypertension
First United Kingdom Heart and Renal Protection (UK-HARP-I) study: Biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease

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Background: Patients with chronic kidney disease are at increased risk for cardiovascular disease, but the efficacy and safety of simvastatin and aspirin are unknown in this patient group. Methods: Patients were randomly assigned in a 2 × 2 factorial design to the administration of: (1) 20 mg of simvastatin daily versus matching placebo, and (2) 100 mg of modified-release aspirin daily versus matching placebo. Results: Overall, 448 patients with chronic kidney disease were randomly assigned (242 predialysis patients with a creatinine level ≥ 1.7 mg/dL [≥150 μmol/L], 73 patients on dialysis therapy, and 133 patients with a functioning transplant). Compliance with study treatments was 80% at 12 months. Allocation to treatment with 100 mg of aspirin daily was not associated with an excess of major bleeds (aspirin, 4 of 225 patients [2%] versus placebo, 6 of 223 patients [3%]; P = not significant [NS]), although there was a 3-fold excess of minor bleeds (34 of 225 [15%] versus 12 of 223 patients [5%]; P = 0.001). Among those with predialysis renal failure or a functioning transplant at baseline, aspirin did not increase the number of patients who progressed to dialysis therapy (7 of 187 [4%] versus 6 of 188 patients [3%]; P = NS) or experienced a greater than 20% increase in creatinine level (63 of 187 patients [34%] versus 56 of 188 patients [30%]; P = NS). After 12 months of follow-up, allocation to 20 mg of simvastatin daily reduced nonfasting total cholesterol levels by 18% (simvastatin, 163 mg/dL [4.22 mmol/L] versus placebo, 196 mg/dL [5.08 mmol/L]; P < 0.0001), directly measured low-density lipoprotein cholesterol levels by 24% (89 mg/dL [2.31 mmol/L] versus 114 mg/dL [2.96 mmol/L]; P < 0.0001), and triglyceride levels by 13% (166 mg/dL [1.87 mmol/L] versus 186 mg/dL [2.10 mmol/L]; P < 0.01), but there was no significant effect on high-density lipoprotein cholesterol levels (2% increase; P = NS). Allocation to simvastatin therapy was not associated with excess risk for abnormal liver function test results or elevated creatine kinase levels. Conclusion: During a 1-year treatment period, simvastatin, 20 mg/d, produced a sustained reduction of approximately one quarter in low-density lipoprotein cholesterol levels, with no evidence of toxicity, and aspirin, 100 mg/d, did not substantially increase the risk for a major bleeding episode. Much larger trials are now needed to assess whether these treatments can prevent vascular events.

Section snippets

Eligibility

Men or women 18 years or older were eligible if: (1) they were a predialysis patient with the most recent serum or plasma creatinine level of 1.7 mg/dL or greater (≥150 μmol/L), a hemodialysis or peritoneal dialysis patient, or had a functioning renal transplant (with any creatinine level); and (2) their own nephrologist and primary care physician did not consider there was a definite indication for (or contraindication to) cholesterol-lowering therapy or aspirin. There was no upper limit to

Study population

The original target sample size was 600 patients, but recruitment was discontinued after an interim analysis of 448 patients showed that the annual rate of major bleeding events was less than anticipated (2.5%), suggesting that continuation would be unlikely to provide much additional information on aspirin-associated bleeding risks. Of 571 patients who attended a screening appointment, 448 patients (78%) were eventually randomized between October 1999 and March 2001. Of randomized patients,

Discussion

In this feasibility study, allocation to treatment with 20 mg of simvastatin daily in patients with CKD reduced LDL cholesterol levels by approximately one quarter, similar to the proportional reduction observed with such regimens in other types of patients irrespective of presenting cholesterol levels.20 This proportional reduction was not significantly different among predialysis, dialysis, and transplant patients, although because the number of dialysis patients was limited, effects of

Acknowledgment

The authors acknowledge the patients who took part in the study and the doctors, nurses, and administrative staff who assisted with its conduct. This report is dedicated to our colleague Dr David Newman (1959 to 2003), whose advice and support was integral to the success of this study and our planning for subsequent studies.

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    The HARP pilot studies and the Study of Heart and Renal Protection (SHARP) were funded by unrestricted grants from Merck & Co. C.B., M.L., J.A., and R.C. each received reimbursement from Merck for travel expenses in connection with various speaking engagements, but as members of the Clinical Trial Service Unit, comply with the Unit’s policy of not accepting honoraria. See Appendix for UK-HARP Pilot Study Investigators.

    Originally published online as doi:10.1053/j.ajkd.2004.11.015 on January 25, 2005.

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