Study of Heart and Renal Protection (SHARP)

This study has been completed.
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Schering-Plough
National Health and Medical Research Council, Australia
British Heart Foundation
Medical Research Council
Information provided by (Responsible Party):
University of Oxford
ClinicalTrials.gov Identifier:
NCT00125593
First received: July 29, 2005
Last updated: January 31, 2012
Last verified: January 2012
Results First Received: August 19, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition: Kidney Disease, Chronic
Interventions: Drug: Simvastatin 20 mg
Drug: Ezetimibe 10mg
Drug: Placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups
  Description
Simvastatin 20mg Plus Ezetimibe 10mg A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Participant Flow:   Overall Study
    Simvastatin 20mg Plus Ezetimibe 10mg     Placebo  
STARTED     4650     4620  
COMPLETED     4549     4517  
NOT COMPLETED     101     103  



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Simvastatin Plus Ezetimibe Once daily tablet
Placebo Once daily tablet
Total Total of all reporting groups

Baseline Measures
    Simvastatin Plus Ezetimibe     Placebo     Total  
Number of Participants  
[units: participants]
  4650     4620     9270  
Age  
[units: Years]
Mean ± Standard Deviation
  62  ± 12     62  ± 12     62  ± 12  
Gender  
[units: participants]
     
Female     1735     1735     3470  
Male     2915     2885     5800  
Renal status  
[units: Participants]
     
On dialysis     1533     1490     3023  
Not on dialysis     3117     3130     6247  



  Outcome Measures
  Hide All Outcome Measures

1.  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   [ Time Frame: Median follow-up 4.9 years ]

Measure Type Primary
Measure Title 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
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Simvastatin Plus Ezetimibe A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Measured Values
    Simvastatin Plus Ezetimibe     Placebo  
Number of Participants Analyzed  
[units: participants]
  4650     4620  
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  
[units: participants]
  526     619  


Statistical Analysis 1 for 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
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0021
Risk Ratio (RR) [4] 0.83
95% Confidence Interval ( 0.74 to 0.94 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  All analyses by intention to treat
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo   [ Time Frame: Median follow-up 4.9 years ]

Measure Type Secondary
Measure Title Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Simvastatin Plus Ezetimibe A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Measured Values
    Simvastatin Plus Ezetimibe     Placebo  
Number of Participants Analyzed  
[units: participants]
  4650     4620  
Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo  
[units: participants]
  701     814  


Statistical Analysis 1 for Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0012
Risk Ratio (RR) [4] 0.85
95% Confidence Interval ( 0.77 to 0.94 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  All analyses by intention to treat
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)   [ Time Frame: Median follow-up 4.9 years ]

Measure Type Secondary
Measure Title Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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)

Reporting Groups
  Description
Simvastatin Plus Ezetimibe A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Measured Values
    Simvastatin Plus Ezetimibe     Placebo  
Number of Participants Analyzed  
[units: participants]
  4193     4191  
Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)  
[units: participants]
  639     749  


Statistical Analysis 1 for Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.001
Risk Ratio (RR) [4] 0.84
95% Confidence Interval ( 0.75 to 0.93 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  All analyses by intention to treat
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo   [ Time Frame: Median follow-up 4.9 years ]

Measure Type Secondary
Measure Title Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Simvastatin Plus Ezetimibe A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Measured Values
    Simvastatin Plus Ezetimibe     Placebo  
Number of Participants Analyzed  
[units: participants]
  4650     4620  
Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo  
[units: participants]
  213     230  


Statistical Analysis 1 for Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.37
Risk Ratio (RR) [4] 0.92
95% Confidence Interval ( 0.76 to 1.11 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  All analyses by intention to treat
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



5.  Secondary:   Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo   [ Time Frame: Median follow-up 4.9 years ]

Measure Type Secondary
Measure Title Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Simvastatin Plus Ezetimibe A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Measured Values
    Simvastatin Plus Ezetimibe     Placebo  
Number of Participants Analyzed  
[units: participants]
  4650     4620  
Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo  
[units: participants]
  131     174  


Statistical Analysis 1 for Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.01
Risk Ratio (RR) [4] 0.75
95% Confidence Interval ( 0.60 to 0.94 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  All analyses by intention to treat
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



6.  Secondary:   Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo   [ Time Frame: Median follow-up 4.9 years ]

Measure Type Secondary
Measure Title Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Simvastatin Plus Ezetimibe A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Measured Values
    Simvastatin Plus Ezetimibe     Placebo  
Number of Participants Analyzed  
[units: participants]
  4650     4620  
Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo  
[units: participants]
  284     352  


Statistical Analysis 1 for Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0036
Risk Ratio (RR) [4] 0.79
95% Confidence Interval ( 0.68 to 0.93 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  All analyses by intention to treat
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo   [ Time Frame: Median follow-up 4.9 years ]

Measure Type Secondary
Measure Title End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Simvastatin Plus Ezetimibe A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets during the first year (active simvastatin plus ezetimibe tablet with a placebo simvastatin tablet). After the first year, all patients took one tablet (active simvastatin 20mg plus ezetimibe 10mg tablet).
Placebo A double-dummy method ensured that patients and study staff were unaware of the treatment allocation, with all patients taking 2 tablets (placebo simvastatin plus ezetimibe tablet with a placebo simvastatin tablet) during the first year. After the first year, all patients took one tablet (placebo simvastatin plus ezetimibe tablet).

Measured Values
    Simvastatin Plus Ezetimibe     Placebo  
Number of Participants Analyzed  
[units: participants]
  3117     3130  
End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo  
[units: participants]
  1057     1084  


Statistical Analysis 1 for End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.41
Risk Ratio (RR) [4] 0.97
95% Confidence Interval ( 0.89 to 1.05 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  All analyses by intention to treat
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  More Information
  Hide More Information

Certain Agreements:  
All Principal Investigators ARE employed by the organization sponsoring the study.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.  


Results Point of Contact:  
Name/Title: Professor Colin Baigent
Organization: Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford
phone: +44 1865 743743
e-mail: colin.baigent@ctsu.ox.ac.uk


Publications of Results:
Other Publications:

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT00125593     History of Changes
Other Study ID Numbers: CTSUSHARP1, ISRCTN54137607, EudraCT - 2004-001156-37, UK CRN 2542
Study First Received: July 29, 2005
Results First Received: August 19, 2011
Last Updated: January 31, 2012
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Germany: Federal Institute for Drugs and Medical Devices