Study of Heart and Renal Protection

Phase 4

Completed

Conditions: Kidney Disease, Chronic

Interventions: Drug: Simvastatin 20 mg
Drug: Placebo
Drug: Ezetimibe 10mg

Registration Number: NCT00125593

Lead Sponsor: University of Oxford

Brief Summary: The chief aim of SHARP was to determine whether lowering blood LDL cholesterol with simvastatin (20mg) plus ezetimibe (10mg) daily could safely reduce the risk of coronary heart disease, non-hemorrhagic stroke and the need for revascularization procedures in patients with chronic kidney disease (CKD). It also aimed to assess whether lowering LDL cholesterol reduced the rate of loss of renal function in people with CKD who had not commenced dialysis treatment.

Detailed Description: The SHARP (Study of Heart and Renal Protection) was a double-blind placebo-controlled trial which aimed to assess the safety and efficacy of reducing LDL cholesterol in more than 9,000 patients with chronic kidney disease (about 3,000 of whom were on dialysis at randomization).

Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo (a subset of these patients had previously received simvastatin 20mg only and were then randomly re-assigned to receive simvastatin 20mg plus ezetimibe 10mg or placebo at one year). Details of the SHARP trial design and methods have been reported previously (reference: Am Heart J 2010; 160:785-94.).

SHARP was overseen by an independent Steering Committee that included nephrologists, cardiologists, clinical trialists, and statisticians, with 2 non-voting observers from the main funder (Merck/Schering-Plough Pharmaceuticals). The independent sponsor was the University of Oxford, and the trial was funded by Merck/Schering-Plough Pharmaceuticals, the Australian National Health and Medical Research Council, the British Heart Foundation and the UK Medical Research Council.

In October 2009, the Steering Committee decided (blind to the effects of study treatment on clinical outcomes) to change the original protocol-specified primary outcome to a revised key outcome of major atherosclerotic events, defined as the combination of non-fatal myocardial infarction, coronary death, ischemic stroke, or any revascularization procedure (i.e. exclusion of non-coronary cardiac deaths and strokes confirmed to be hemorrhagic from the original major vascular event outcome). These and other changes are described in the revised statistical analysis plan for SHARP (reference: Am Heart J 2010; 160:785-94.). Accordingly, the chief emphasis of the published results (reference: Lancet 2011; 377:2181-92) is on the revised pre-specified key outcome of first major atherosclerotic events.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 9438

Inclusion Criteria

History of chronic kidney disease (CKD): either patients who are pre-dialysis (with a plasma or serum creatinine greater than or equal to 150 micromol/l [greater than or equal to 1.7 mg/dl] in men, or greater than or equal to 130 micromol/l [greater than or equal to 1.5 mg/dl] in women); or patients on dialysis (hemodialysis or peritoneal dialysis)
Men or women aged greater than or equal to 40 years

Exclusion Criteria

Definite history of myocardial infarction or coronary revascularization procedure
Functioning renal transplant, or living donor-related transplant planned
Less than 2 months since presentation as an acute uraemic emergency (but could be entered later, if appropriate)
Definite history of chronic liver disease, or abnormal liver function (i.e. alanine aminotransferase [ALT] greater than 1.5 x upper limit of normal [ULN] or, if ALT not available, aspartate aminotransferase [AST] greater than 1.5 x ULN). (Note: Patients with a history of hepatitis were eligible provided these limits were not exceeded.)
Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) greater than 3 x ULN
Definite previous adverse reaction to a statin or to ezetimibe
Concurrent treatment with a contraindicated drug. (Note: Patients who were temporarily taking such drugs could have been re-screened for participation in the study when they discontinued them, if appropriate.) These contraindicated drugs included: HMG-CoA reductase inhibitor ("statin"); fibric acid derivative ("fibrate"); nicotinic acid; macrolide antibiotic (erythromycin, clarithromycin); systemic use of imidazole or triazole antifungals (e.g. itraconazole, ketoconazole); protease-inhibitors (e.g. antiretroviral drugs for HIV infection); nefazodone; ciclosporin
Child-bearing potential (i.e. premenopausal woman who was not using a reliable method of contraception)
Known to be poorly compliant with clinic visits or prescribed medication
Medical history that might have limited 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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Simvastatin 20mg plus Ezetimibe 10mg	Simvastatin 20 mg	Simvastatin 20mg plus ezetimibe 10mg = Arm 2. A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all Arm 2 patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all Arm 2 patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Simvastatin 20mg plus Ezetimibe 10mg	Ezetimibe 10mg	Simvastatin 20mg plus ezetimibe 10mg = Arm 2. A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all Arm 2 patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all Arm 2 patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo	Placebo	Placebo = Arm 1. A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all Arm 1 patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all Arm 1 patients took one tablet (placebo simvastatin plus ezetimibe tablet).
Simvastatin 20mg	Simvastatin 20 mg	Simvastatin 20mg alone = Arm 3. After 1 year, those initially allocated to Arm 3 were re-randomized to simvastatin 20mg plus ezetimibe 10mg (Arm 3b) daily or placebo (Arm 3a). A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with Arm 3 patients taking 2 tablets (a placebo simvastatin plus ezetimibe tablet with an active simvastatin tablet) during the first year. After the first year, all Arm 3a and Arm 3b patients took one tablet (active or placebo simvastatin plus ezetimibe tablet).

Primary Outcome Measures

Name	Time	Method
Key Outcome as Per Statistical Analysis Plan = Major Atherosclerotic Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	Median follow-up 4.9 years	Major atherosclerotic events defined as non-fatal myocardial infarction or coronary death, non-hemorrhagic stroke, or any arterial revascularization procedure (excluding dialysis access procedures). Numbers provided = number of patients with events.

Secondary Outcome Measures

Name	Time	Method
Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	Median follow-up 4.9 years	Major vascular events defined as non-fatal myocardial infarction or cardiac death, any stroke, or any arterial revascularization procedure (excluding dialysis access procedures). Numbers provided = number of patients with events.
Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)	Median follow-up 4.9 years	Major vascular events defined as non-fatal myocardial infarction or cardiac death, any stroke, or any arterial revascularization procedure (excluding dialysis access procedures). Numbers provided = number of patients with events.
Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	Median follow-up 4.9 years	Major coronary events defined as coronary death or non-fatal myocardial infarction. Myocardial infarction adjudicated based on the presence of serial changes in cardiac biomarkers (e.g. troponin, creatine kinase), typical ECG changes and typical cardiac symptoms. If myocardial infarction was fatal and post-mortem examination findings were available, this information was also assessed. All potential coronary events were adjudicated, using pre-specified objective criteria, by clinicians blinded to study treatment allocation and lipid levels. Numbers provided = number of patients with events.
Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	Median follow-up 4.9 years	Stroke was defined as rapid onset of focal or global neurological deficit, with duration greater than 24 hours. Clinical notes and brain imaging were sought to determine the stroke etiology, and if the stroke was fatal and post-mortem examination findings were available, this information was also assessed. All potential stroke events (including transient ischemic attack and intracerebral hemorrhage) were adjudicated, using pre-specified objective criteria, by clinicians blinded to study treatment allocation and lipid levels. Numbers provided = number of patients with events.
Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	Median follow-up 4.9 years	Revascularization included any arterial revascularization procedure, whether surgical or percutaneous, but excluded revascularization performed for hemodialysis vascular access (e.g. fistuloplasty) or to the donor kidney transplant artery. Revascularization included amputations for vascular disease (rather than for trauma or infection). All potential revascularization events (including angiography) were adjudicated, using pre-specified objective criteria, by clinicians blinded to study treatment allocation and lipid levels. Numbers provided = number of patients with events.
End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo	Median follow-up 4.9 years	End-stage renal disease was defined as initiation of maintenance dialysis or renal transplantation. Temporary dialysis was excluded. All potential dialysis and transplant events were adjudicated, using pre-specified objective criteria, by clinicians blinded to study treatment allocation and lipid levels. Numbers provided = number of patients with events.