Study of Heart and Renal Protection - SHARP

Jun 09, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.
Date Presented:
01/01/2010
Date Published:
01/01/2011
Date Updated:
06/09/2011
Original Posted Date:
06/09/2011
References

Description:

Studies on low-density lipoprotein (LDL) lowering in patients with chronic kidney disease, but no overt coronary disease, have been inconclusive. The current trial sought to compare outcomes after randomization to simvastatin/ezetimibe or placebo in patients with chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] < 30 ml/min).

Hypothesis:

Simvastatin/ezetimibe would be superior to placebo in reducing LDL cholesterol and major vascular events in adult patients with CKD.

Study Design

  • Blinded
  • Placebo Controlled
  • Randomized
  • Stratified
  • Parallel

Patient Populations:

  • History of CKD
    ○ Predialysis (blood creatinine ≥1.7 mg/dl [≥150 μmol/L] in men or ≥1.5 mg/dl [≥130 μmol/L] in women at both the most recent routine clinic visit and the study screening visit), or
    ○ Dialysis (hemodialysis or peritoneal dialysis)
  • No history of MI or revascularization
  • LDL lowering treatment not definitely indicated or contraindicated
  • Age ≥40 years

    Number of enrollees: 9,438
    Duration of follow-up: median 4.9 years
    Mean patient age: 62 years
    Percentage female: 37%

Exclusions:

  • Definite history of MI or coronary revascularization procedure
  • Functioning renal transplant or living donor renal transplant planned
  • Less than 2 months since presentation as an acute uremic emergency
  • Definite history of chronic liver disease or abnormal liver function (i.e., ALT N1.5× ULN or, if ALT not available, AST N1.5× ULN) (patients with a history of hepatitis are eligible if these limits are not exceeded)
  • Evidence of active inflammatory muscle disease (e.g., dermatomyositis, polymyositis) or creatine kinase N3× ULN
  • Definite previous adverse reaction to a statin or to ezetimibe
  • Concurrent treatment with a contraindicated drug:
    ○ Hydroxymethylglutaryl–coenzyme A reductase inhibitor (“statin”)
    ○ Ezetimibe
    ○ Fibric acid derivative (“fibrate”)
    ○ Nicotinic acid
    ○ Cyclosporin
    ○ 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
  • Child-bearing potential (i.e., premenopausal woman who is not using a reliable method of contraception)
  • Known to be poorly compliant with clinic visits or prescribed medication
  • Medical history that might limit the individual’s ability to take the trial treatments for the duration of the study (e.g., severe respiratory disease, history of cancer other than nonmelanoma skin cancer, or recent history of alcohol or substance misuse)

Primary Endpoints:

  • Major atherosclerotic events (coronary death, myocardial infarction [MI], nonhemorrhagic stroke, or any revascularization)

Secondary Endpoints:

  • Major vascular events (cardiac death, nonfatal MI, coronary revascularization, or any stroke)
  • End-stage renal disease with need for dialysis or transplant

Drug/Procedures Used:

Using a “double-dummy” method to maintain blinding for both patients and physicians, patients were randomized in a ratio of 4:4:1 to ezetimibe/simvastatin 10/20 mg daily versus matching placebo versus simvastatin 20 mg daily. After 1 year, patients initially allocated to simvastatin 20 mg daily alone (who formed a comparison group for the assessment of any early adverse effects of ezetimibe) were re-randomized to ezetimibe/simvastatin 10/20 mg daily versus placebo for the remainder of the scheduled study treatment period. A run-in phase of 6 weeks existed, wherein patients with <90% compliance or those unlikely to reliably follow-up were excluded.

Concomitant Medications:

Antiplatelet therapy (22%), angiotensin-converting enzyme inhibitor (35%), angiotensin-receptor blocker (23%), beta-blocker (37%)

Principal Findings:

A total of 9,438 patients were randomized, 4,193 to ezetimibe/simvastatin, 1,054 to simvastatin and 4,191 to placebo. After 1 year, 886 of the simvastatin patients were re-randomized to ezetimibe/simvastatin or placebo, resulting in 4,650 patients in the ezetimibe/simvastatin arm, and 4,620 in the placebo arm for analysis.

Of these patients, 3,023 (33%) were on dialysis at the time of randomization.The mean eGFR was 26.6 ml/min, with a median urinary albumin:creatinine ratio of about 206 mg/g. The etiology of renal failure was diabetes in 15%, hypertensive/renovascular disease in 20%, glomerulonephritis in 15%, and cystic kidney disease in 12%. Mean systolic blood pressure and diastolic blood pressure at baseline were 139 and 79 mm Hg, respectively, with a mean body mass index of 27.1 kg/m2. Diabetes was present in 23%, peripheral arterial disease in 6%, angina in 3%, and cerebrovascular disease in 7%. The majority of patients (72%) were Caucasian. Baseline total cholesterol was 189 mg/dl, LDL was 108 mg/dl, and high-density lipoprotein (HDL) was 43 mg/dl. 

After a median follow-up of 4.9 years, patients randomized to ezetimibe/simvastatin had a 17% reduction in major atherosclerotic events compared with the placebo group (11.3% vs. 13.4%, hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.74-0.94, p = 0.0021). The secondary outcome of major vascular events was similarly reduced (15.1% vs. 17.6%, p = 0.0012), as were the incidences of nonhemorrhagic stroke (2.8% vs. 3.8%, p = 0.01) and arterial revascularizations (6.1% vs. 7.6%, p = 0.0036). Individual endpoints including major coronary event (4.6% vs. 5.0%) and hemorrhagic stroke (1.0% vs. 0.8%) were similar between the two arms. Among the 6,247 patients not on dialysis at baseline, the main renal outcome of end-stage renal disease requiring dialysis or transplant was similar between the two arms (33.9% vs. 34.6%, HR 0.97, 95% CI 0.89-1.05, p = 0.41).

The incidence of cancer was similar between the two arms over the course of follow-up (9.4% vs. 9.5%, p = 0.89). Incidence of side effects, including any muscle pain (21.3% vs. 20.8%), significant myopathy (CK 10 to 40 x ULN) (0.4% vs. 0.3%), and persistent 3x upper limit of normal (ULN) elevation of liver enzymes (0.6% vs. 0.6%), was similar between the two arms.

Interpretation:

The results of the SHARP trial indicate that ezetimibe/simvastatin is superior to placebo in reducing LDL cholesterol and in reducing atherosclerotic and major vascular events over a median follow-up of 4.9 years.

The ezetimibe/simvastatin combination (Zetia) has been under scrutiny since the publication of the ENHANCE trial showed no significant improvement in vascular events in patients at high risk despite a significant reduction in LDL, as compared with simvastatin alone. Two trials, 4D and AURORA, noted no consistent improvement in major vascular events, as compared with placebo in patients with CKD who did not have overt coronary artery disease. However, the current trial suggests that the ezetimibe/simvastatin combination reduced LDL cholesterol significantly in this patient population, and also reduced major vascular events.

One advantage of the combination over a statin alone is that greater reductions in LDL cholesterol can be achieved with lower doses of a statin (20 mg in this trial), since higher doses of statins can cause greater myopathy in patients with CKD. However, since the statin alone arm was stopped after 1 year in this trial, it remains unknown if the combination of ezetimibe/statin is superior to statin therapy alone.


References:

Baigent C, Landray MJ, Reith C, et al., on behalf of the 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 9:[Epub ahead of print].

Presented by Drs. Colin Baigent and Martin Landray at the American Society of Nephrology’s Renal Week, Denver, CO, November 20, 2010.

To view the SHARP press release, slide set, and more, go to www.sharpinfo.org.

Keywords: Coronary Artery Disease, Kidney Diseases, Cystic, Follow-Up Studies, Blood Pressure, Peripheral Arterial Disease, Creatinine, Renal Dialysis, Azetidines, Peritoneal Dialysis, Confidence Intervals, Myalgia, Stroke, Kidney Failure, Chronic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Lipoproteins, LDL, Drug Combinations, Body Mass Index, Liver, Glomerular Filtration Rate, Lipoproteins, HDL, Glomerulonephritis, Diabetes Mellitus, Renal Insufficiency, Chronic


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