Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
9438 participants
INTERVENTIONAL
2003-06-30
2010-08-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
QUADRUPLE
Study Groups
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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).
Placebo
Once daily
Simvastatin 20mg plus 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).
Simvastatin 20 mg
Once daily
Ezetimibe 10mg
Once daily
Simvastatin 20mg
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).
Simvastatin 20 mg
Once daily
Interventions
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Simvastatin 20 mg
Once daily
Ezetimibe 10mg
Once daily
Placebo
Once daily
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Men or women aged greater than or equal to 40 years
Exclusion Criteria
* 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)
40 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Schering-Plough
INDUSTRY
National Health and Medical Research Council, Australia
OTHER
British Heart Foundation
OTHER
Medical Research Council
OTHER_GOV
University of Oxford
OTHER
Responsible Party
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Principal Investigators
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Colin Baigent, FRCP, FFPH
Role: PRINCIPAL_INVESTIGATOR
Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford
Martin J Landray, PhD, FRCP
Role: PRINCIPAL_INVESTIGATOR
Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford
Locations
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Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford
Oxford, , United Kingdom
Countries
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References
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Baigent C, Landray M, Leaper C, Altmann P, Armitage J, Baxter A, Cairns HS, Collins R, Foley RN, Frighi V, Kourellias K, Ratcliffe PJ, Rogerson M, Scoble JE, Tomson CR, Warwick G, Wheeler DC. First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis. 2005 Mar;45(3):473-84. doi: 10.1053/j.ajkd.2004.11.015.
Landray M, Baigent C, Leaper C, Adu D, Altmann P, Armitage J, Ball S, Baxter A, Blackwell L, Cairns HS, Carr S, Collins R, Kourellias K, Rogerson M, Scoble JE, Tomson CR, Warwick G, Wheeler DC. The second United Kingdom Heart and Renal Protection (UK-HARP-II) Study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD. Am J Kidney Dis. 2006 Mar;47(3):385-95. doi: 10.1053/j.ajkd.2005.11.018.
Sharp Collaborative Group. Study of Heart and Renal 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 Nov;160(5):785-794.e10. doi: 10.1016/j.ahj.2010.08.012. Epub 2010 Sep 18.
Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellstrom B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Gronhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011 Jun 25;377(9784):2181-92. doi: 10.1016/S0140-6736(11)60739-3. Epub 2011 Jun 12.
Tunnicliffe DJ, Palmer SC, Cashmore BA, Saglimbene VM, Krishnasamy R, Lambert K, Johnson DW, Craig JC, Strippoli GF. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2023 Nov 29;11(11):CD007784. doi: 10.1002/14651858.CD007784.pub3.
Sukkar L, Talbot B, Jun M, Dempsey E, Walker R, Hooi L, Cass A, Jardine M, Gallagher M. Protocol for the Study of Heart and Renal Protection-Extended Review: Additional 5-Year Follow-up of the Australian, New Zealand, and Malaysian SHARP Cohort. Can J Kidney Health Dis. 2019 Oct 14;6:2054358119879896. doi: 10.1177/2054358119879896. eCollection 2019.
Schlackow I, Kent S, Herrington W, Emberson J, Haynes R, Reith C, Collins R, Landray MJ, Gray A, Baigent C, Mihaylova B; SHARP Collaborative Group. Cost-effectiveness of lipid lowering with statins and ezetimibe in chronic kidney disease. Kidney Int. 2019 Jul;96(1):170-179. doi: 10.1016/j.kint.2019.01.028. Epub 2019 Mar 12.
Schlackow I, Kent S, Herrington W, Emberson J, Haynes R, Reith C, Wanner C, Fellstrom B, Gray A, Landray MJ, Baigent C, Mihaylova B; SHARP Collaborative Group. A policy model of cardiovascular disease in moderate-to-advanced chronic kidney disease. Heart. 2017 Dec;103(23):1880-1890. doi: 10.1136/heartjnl-2016-310970. Epub 2017 Aug 5.
Reith C, Staplin N, Herrington WG, Stevens W, Emberson J, Haynes R, Mafham M, Armitage J, Cass A, Craig JC, Jiang L, Pedersen T, Baigent C, Landray MJ; SHARP Collaborative Group. Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection. BMC Nephrol. 2017 May 1;18(1):147. doi: 10.1186/s12882-017-0545-2.
Herrington W, Staplin N, Judge PK, Mafham M, Emberson J, Haynes R, Wheeler DC, Walker R, Tomson C, Agodoa L, Wiecek A, Lewington S, Reith CA, Landray MJ, Baigent C; SHARP Collaborative Group. Evidence for Reverse Causality in the Association Between Blood Pressure and Cardiovascular Risk in Patients With Chronic Kidney Disease. Hypertension. 2017 Feb;69(2):314-322. doi: 10.1161/HYPERTENSIONAHA.116.08386. Epub 2016 Dec 27.
Morton RL, Schlackow I, Staplin N, Gray A, Cass A, Haynes R, Emberson J, Herrington W, Landray MJ, Baigent C, Mihaylova B; SHARP Collaborative Group. Impact of Educational Attainment on Health Outcomes in Moderate to Severe CKD. Am J Kidney Dis. 2016 Jan;67(1):31-9. doi: 10.1053/j.ajkd.2015.07.021. Epub 2015 Sep 16.
Peto R, Emberson J, Landray M, Baigent C, Collins R, Clare R, Califf R. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008 Sep 25;359(13):1357-66. doi: 10.1056/NEJMsa0806603. Epub 2008 Sep 2.
Related Links
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SHARP homepage
Other Identifiers
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ISRCTN54137607
Identifier Type: OTHER
Identifier Source: secondary_id
EudraCT - 2004-001156-37
Identifier Type: OTHER
Identifier Source: secondary_id
UK CRN 2542
Identifier Type: OTHER
Identifier Source: secondary_id
CTSUSHARP1
Identifier Type: -
Identifier Source: org_study_id
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