Trial Outcomes & Findings for Study of Heart and Renal Protection (NCT NCT00125593)

NCT ID: NCT00125593

Last Updated: 2012-02-01

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

9438 participants

Primary outcome timeframe

Median follow-up 4.9 years

Results posted on

2012-02-01

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	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).
Overall Study STARTED	4650	4620
Overall Study COMPLETED	4549	4517
Overall Study NOT COMPLETED	101	103

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of Heart and Renal Protection

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Simvastatin Plus Ezetimibe n=4650 Participants Once daily tablet	Placebo n=4620 Participants Once daily tablet	Total n=9270 Participants Total of all reporting groups
Age Continuous	62 Years STANDARD_DEVIATION 12 • n=5 Participants	62 Years STANDARD_DEVIATION 12 • n=7 Participants	62 Years STANDARD_DEVIATION 12 • n=5 Participants
Sex: Female, Male Female	1735 Participants n=5 Participants	1735 Participants n=7 Participants	3470 Participants n=5 Participants
Sex: Female, Male Male	2915 Participants n=5 Participants	2885 Participants n=7 Participants	5800 Participants n=5 Participants
Renal status On dialysis	1533 Participants n=5 Participants	1490 Participants n=7 Participants	3023 Participants n=5 Participants
Renal status Not on dialysis	3117 Participants n=5 Participants	3130 Participants n=7 Participants	6247 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Simvastatin Plus Ezetimibe n=4650 Participants 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 n=4620 Participants 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).
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	619 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Simvastatin Plus Ezetimibe n=4650 Participants 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 n=4620 Participants 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).
Major Vascular Events Analyzed Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	701 participants	814 participants

SECONDARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	Simvastatin Plus Ezetimibe n=4193 Participants 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 n=4191 Participants 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).
Major Vascular Events Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)	639 participants	749 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Simvastatin Plus Ezetimibe n=4650 Participants 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 n=4620 Participants 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).
Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	213 participants	230 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Simvastatin Plus Ezetimibe n=4650 Participants 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 n=4620 Participants 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).
Non-hemorrhagic Stroke Among All of Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	131 participants	174 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Simvastatin Plus Ezetimibe n=4650 Participants 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 n=4620 Participants 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).
Coronary or Non-coronary Revascularization Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo	284 participants	352 participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Simvastatin Plus Ezetimibe n=3117 Participants 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 n=3130 Participants 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).
End-stage Renal Disease Among All Patients Not on Dialysis at the Time of Randomization to Simvastatin Plus Ezetimibe Versus Placebo	1057 participants	1084 participants

Adverse Events

Simvastatin Plus Ezetimibe

Serious events: 1142 serious events

Other events: 992 other events

Deaths: 0 deaths

Placebo

Serious events: 1115 serious events

Other events: 960 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Simvastatin Plus Ezetimibe n=4650 participants at risk Once daily tablet	Placebo n=4620 participants at risk Once daily tablet
Vascular disorders Vascular death	7.8% 361/4650 • Median follow-up 4.9 years	8.4% 388/4620 • Median follow-up 4.9 years
General disorders Non-vascular deaths	14.4% 668/4650 • Median follow-up 4.9 years	13.2% 612/4620 • Median follow-up 4.9 years
General disorders Unknown causes of death	2.4% 113/4650 • Median follow-up 4.9 years	2.5% 115/4620 • Median follow-up 4.9 years

Other adverse events

Other adverse events
Measure	Simvastatin Plus Ezetimibe n=4650 participants at risk Once daily tablet	Placebo n=4620 participants at risk Once daily tablet
Musculoskeletal and connective tissue disorders Muscle pain	21.3% 992/4650 • Median follow-up 4.9 years	20.8% 960/4620 • Median follow-up 4.9 years

Additional Information

Professor Colin Baigent

Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford

Phone: +44 1865 743743

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place