Study of Heart and Renal Protection

NCT00125593 | Completed Phase 4 Results DMC

• 4 other identifiers: CTSUSHARP1ISRCTN54137607EudraCT - 2004-001156-37UK CRN 2542
• Study Type: interventional
• Target: 9,438
• Locations: 1 country
• Sites: 1

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.

Conditions

Kidney Disease, Chronic

Keywords

Kidney Disease, Chronic; LDL cholesterol; simvastatin; ezetimibe; cardiovascular disease; atherosclerosis

Outcome Measures

Primary Outcomes (1)

• 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.

  Median follow-up 4.9 years

Secondary Outcomes (6)

• 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 Analyzed Amongst Patients Initially Randomized to Simvastatin Plus Ezetimibe Versus Placebo (Original Protocol-defined Primary Outcome)

  Median follow-up 4.9 years

• Major Coronary Events Among All Patients Ever Randomized to Simvastatin Plus Ezetimibe Versus All Patients Allocated to Placebo

  Median follow-up 4.9 years

• 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

• 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

Study Arms (3)

Placebo

PLACEBO COMPARATOR

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).

Drug: Placebo

Simvastatin 20mg plus Ezetimibe 10mg

ACTIVE COMPARATOR

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).

Drug: Simvastatin 20 mg; Drug: Ezetimibe 10mg

Simvastatin 20mg

OTHER

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).

Drug: Simvastatin 20 mg

Interventions

Simvastatin 20 mg DRUG

Once daily

Also known as: Zocor

Simvastatin 20mg; Simvastatin 20mg plus Ezetimibe 10mg

Ezetimibe 10mg DRUG

Once daily

Also known as: Ezetrol, Zetia, Vytorin (simvastatin plus ezetimibe)

Simvastatin 20mg plus Ezetimibe 10mg

Placebo DRUG

Once daily

Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Oxford: lead
• Merck Sharp & Dohme LLC: collaborator
• Schering-Plough: collaborator
• National Health and Medical Research Council, Australia: collaborator
• British Heart Foundation: collaborator
• Medical Research Council: collaborator

Study Sites (1)

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

Oxford, OX3 7LF, United Kingdom

Location

Related Publications (12)

• 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.

  PMID: 15754269 BACKGROUND

• 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.

  PMID: 16490616 BACKGROUND

• 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.

  PMID: 21095263 BACKGROUND

• 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.

  PMID: 21663949 RESULT

• 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.

  PMID: 38018702 DERIVED

• 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.

  PMID: 31662874 DERIVED

• 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.

  PMID: 31005271 DERIVED

• 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.

  PMID: 28780579 DERIVED

• 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.

  PMID: 28460629 DERIVED

• 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.

  PMID: 28028192 DERIVED

• 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.

  PMID: 26385817 DERIVED

• 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.

  PMID: 18765432 DERIVED

Related Links

• SHARP homepage

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Cardiovascular Diseases; Atherosclerosis

Interventions

Simvastatin; Ezetimibe; Ezetimibe, Simvastatin Drug Combination

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Professor Colin Baigent
• Organization: Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford

colin.baigent@ctsu.ox.ac.uk

+44 1865 743743

Study Officials

• Colin Baigent, FRCP, FFPH

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

  PRINCIPAL INVESTIGATOR

• Martin J Landray, PhD, FRCP

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2005
• First Posted: August 1, 2005
• Study Start: June 1, 2003
• Primary Completion: August 1, 2010
• Study Completion: August 1, 2010
• Last Updated: February 1, 2012
• Results First Posted: February 1, 2012

Record last verified: 2012-01

Locations

GB (1)