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.
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 x 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 > or = 1.7 mg/dL [> or =150 micromol/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.


CONCLUSIONS
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.
Baigent
Colin
C
Clinical Trial Service Unit, Oxford University, Oxford, UK. colin.baigent@ctsu.ox.ac.uk
Landray
Martin
M
Leaper
Craig
C
Altmann
Paul
P
Armitage
Jane
J
Baxter
Alex
A
Cairns
Hugh S
HS
Collins
Rory
R
Foley
Robert N
RN
Frighi
Valeria
V
Kourellias
Karen
K
Ratcliffe
Peter J
PJ
Rogerson
Mary
M
Scoble
John E
JE
Tomson
Charles R V
CR
Warwick
Graham
G
Wheeler
David C
DC
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control*; D008078:Cholesterol, LDL / Q000097:blood; D002908:Chronic Disease; D003402:Creatine Kinase / Q000097:blood; D052283:Creatine Kinase, MM Form; D003404:Creatinine / Q000097:blood; D003928:Diabetic Nephropathies / Q000097:blood / Q000150:complications; D018450:Disease Progression; D005240:Feasibility Studies; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D007527:Isoenzymes / Q000097:blood; D007674:Kidney Diseases / Q000097:blood / Q000150:complications* / Q000601:surgery / Q000628:therapy; D016030:Kidney Transplantation; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006435:Renal Dialysis / Q000706:statistics & numerical data; D017582:Renal Replacement Therapy; D019821:Simvastatin / Q000009:adverse effects / Q000627:therapeutic use*; D016037:Single-Blind Method; D019851:Thrombophilia / Q000150:complications / Q000188:drug therapy*; D016896:Treatment Outcome
D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D008055:Lipids; D010975:Platelet Aggregation Inhibitors; D019821:Simvastatin; D003404:Creatinine; D000410:Alanine Transaminase; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form; D001241:Aspirin