Kidney Disease, Chronic
Conditions
Keywords
Kidney Disease, Chronic, LDL cholesterol, simvastatin, ezetimibe, cardiovascular disease, atherosclerosis
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.
Interventions
Sponsors
Merck Sharp & Dohme LLC
Schering-Plough
National Health and Medical Research Council, Australia
British Heart Foundation
Medical Research Council
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United Kingdom
Participant flow
Recruitment details
SHARP was conducted in 380 centres in 18 countries: Austria, Australia, Canada, China, The Czech Republic, Denmark, Finland, France, Germany, Malaysia, The Netherlands, New Zealand, Norway, Poland, Sweden, Thailand, the United Kingdom and the United States of America. Recruitment occurred between 2003 and 2006.
Pre-assignment details
Run-in period between screening and randomization of \ 6 weeks duration. 11792 patients screened and 9438 randomized to the initial 3 arms. Overall 9270 patients were randomly assigned to simvastatin plus ezetimibe (4650 patients, 4193 initially plus 457 after first year) versus placebo (4620 patients, 4191 initially plus 429 after first year).
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin Plus Ezetimibe Once daily tablet | 4,650 |
| Placebo Once daily tablet | 4,620 |
| Total | 9,270 |
Baseline characteristics
| Characteristic | Simvastatin Plus Ezetimibe | Placebo | Total |
|---|---|---|---|
| Age Continuous | 62 Years STANDARD_DEVIATION 12 | 62 Years STANDARD_DEVIATION 12 | 62 Years STANDARD_DEVIATION 12 |
| Renal status Not on dialysis | 3117 Participants | 3130 Participants | 6247 Participants |
| Renal status On dialysis | 1533 Participants | 1490 Participants | 3023 Participants |
| Sex: Female, Male Female | 1735 Participants | 1735 Participants | 3470 Participants |
| Sex: Female, Male Male | 2915 Participants | 2885 Participants | 5800 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 992 / 4,650 | 960 / 4,620 |
| serious Total, serious adverse events | 1,142 / 4,650 | 1,115 / 4,620 |
Outcome results
Primary
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
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.
Time frame: Median follow-up 4.9 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Simvastatin Plus Ezetimibe | 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 | 526 participants |
| Placebo | 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 | 619 participants |
Comparison: All analyses by intention to treatp-value: 0.002195% CI: [0.74, 0.94]Log Rank
Secondary
Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
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.
Time frame: Median follow-up 4.9 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Simvastatin Plus Ezetimibe | Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 284 participants |
| Placebo | Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 352 participants |
Comparison: All analyses by intention to treatp-value: 0.003695% CI: [0.68, 0.93]Log Rank
Secondary
End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo
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.
Time frame: Median follow-up 4.9 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Simvastatin Plus Ezetimibe | End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo | 1057 participants |
| Placebo | End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo | 1084 participants |
Comparison: All analyses by intention to treatp-value: 0.4195% CI: [0.89, 1.05]Log Rank
Secondary
Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
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.
Time frame: Median follow-up 4.9 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Simvastatin Plus Ezetimibe | Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 213 participants |
| Placebo | Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 230 participants |
Comparison: All analyses by intention to treatp-value: 0.3795% CI: [0.76, 1.11]Log Rank
Secondary
Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
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.
Time frame: Median follow-up 4.9 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Simvastatin Plus Ezetimibe | Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 701 participants |
| Placebo | Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 814 participants |
Comparison: All analyses by intention to treatp-value: 0.001295% CI: [0.77, 0.94]Log Rank
Secondary
Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)
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.
Time frame: Median follow-up 4.9 years
Population: Includes only those patients initially randomized to simvastatin plus ezetimibe versus placebo (as opposed to all patients ever randomized to simvastatin plus ezetimibe versus all patients allocated placebo)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Simvastatin Plus Ezetimibe | Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome) | 639 participants |
| Placebo | Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome) | 749 participants |
Comparison: All analyses by intention to treatp-value: 0.00195% CI: [0.75, 0.93]Log Rank
Secondary
Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
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.
Time frame: Median follow-up 4.9 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Simvastatin Plus Ezetimibe | Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 131 participants |
| Placebo | Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo | 174 participants |
Comparison: All analyses by intention to treatp-value: 0.0195% CI: [0.6, 0.94]Log Rank