Prevention of vascular disease in chronic kidney disease patients Circulatory System Vascular disease
Conditions
Interventions
Following a 6-week run-in phase, participants are initially randomised to:
Arm 1: placebo, OR
Arm 2: ezetimibe 10 mg + simvastatin 20 mg daily, OR
Arm 3
Sponsors
University of Oxford (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. History of chronic kidney disease (CKD): either patients who are pre-dialysis (with a plasma or serum creatinine greater than or equal to 150 µ/l [greater than or equal to 1.7 mg/dl] in men, or greater than or equal to 130 µ/l [greater than or equal to 1.5 mg/dl] in women); or patients on dialysis (haemodialysis or peritoneal dialysis) 2. Men or women aged greater than or equal to 40 years
Exclusion criteria
Exclusion criteria: 1. Definite history of myocardial infarction or coronary revascularisation procedure 2. Functioning renal transplant, or living donor-related transplant planned 3. Less than 2 months since presentation as an acute uraemic emergency (but may be entered later, if appropriate) 4. Definite history of chronic liver disease, or abnormal liver function (i.e. alanine aminotransferase [ALT] >1.5 x upper limit of normal [ULN] or, if ALT not available, aspartate aminotransferase [AST] >1.5 x ULN). (Note: Patients with a history of hepatitis are eligible provided these limits are not exceeded). 5. Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) >3 x ULN 6. Definite previous adverse reaction to a statin or to ezetimibe 7. Concurrent treatment with a contraindicated drug (Note: Patients who are temporarily taking such drugs may be re-screened for participation in the study when they discontinue them, if appropriate). These contraindicated drugs include: a. HMG-CoA reductase inhibitor ('statin') b. Fibric acid derivative ('fibrate') c. Nicotinic acid d. Macrolide antibiotic (erythromycin, clarithromycin) e. Systemic use of imidazole or triazole antifungals (e.g. itraconazole, ketoconazole) f. Protease-inhibitors (e.g. antiretroviral drugs for human immunodeficiency virus [HIV] infection) g. Nefazodone h. Ciclosporin 8. Child-bearing potential (i.e. premenopausal woman who is not using a reliable method of contraception) 9. Known to be poorly compliant with clinic visits or prescribed medication 10. Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease, history of cancer other than non-melanoma skin cancer, or recent history of alcohol or substance misuse)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Major vascular events (defined as non-fatal myocardial infarction or cardiac death, non-fatal or fatal stroke, or revascularisation) at end of study Please note, in October 2009, the Steering Committee decided to change the primary outcome to major atherosclerotic events, defined as the combination of MI, coronary death, ischaemic stroke, or any revascularization procedure (ie, exclusion of non-coronary cardiac deaths and strokes confirmed to be haemorrhagic from the original major vascular event outcome). The independent sponsor (University of Oxford) was required by its contract with the main funder (Merck/Schering-Plough) to seek its formal agreement to any protocol change, but the funder declined to approve the changes agreed by the Steering Committee. Although it was therefore not possible to revise the protocol accordingly, the Steering Committee was free to change the statistical analysis plan as it considered appropriate whilst it remained blind to the effects of treatment on efficacy end points. The 'key outcome' was therefore changed to 'Major Atherosclerotic Events' by the Steering Committee whilst still blind to the effects of treatment on clinical outcomes. This is described in the following paper: SHARP Collaborative Group. Study of Heart and Real Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. Am Heart J 2010; 160: 785-94 (http://www.ncbi.nlm.nih.gov/pubmed/21095263). | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Major vascular events at end of study 2. Major cardiac events (non-fatal myocardial infarction [MI] or cardiac death) at end of study 3. Stroke (fatal or non-fatal) at end of study 4. Coronary or non-coronary revascularisation at end of study 5. Mortality, both overall and within particular categories at end of study 6. Hospital admission for angina at end of study 7. End-stage renal disease (need for long-term dialysis or transplantation) at end of study 8. End-stage renal disease or death from any cause at end of study | — |
Countries
Australia, Austria, Canada, China, Czech Republic, Denmark, Finland, France, Germany, Malaysia, Netherlands, New Zealand, Norway, Poland, Sweden, Thailand, United Kingdom, United States of America
Outcome results
None listed