In a new investigational study sponsored by Merck (known as MSD outside of the US and Canada), 'Inegy'® (ezetimibe/simvastatin) 10/20 mg reduced the incidence of first major vascular events (defined as non-fatal heart attacks or cardiac death, stroke or any revascularisation procedure) by a highly statistically significant 16.0 percent compared to placebo (p=0.0012). This was the pre-specified primary endpoint of the study. The SHARP (Study of Heart and Renal Protection) study involved more than 9,000 patients who, on average, had advanced or end-stage chronic kidney disease (CKD), and is the first prospective clinical study in patients with CKD to demonstrate the benefit of lowering LDL (bad) cholesterol on major vascular events. The results were presented today during Renal Week, the American Society of Nephrology's annual meeting, by Professor Colin Baigent, F.F.P.H., F.R.C.P., and Dr. Martin Landray, Ph.D., F.R.C.P., the principal investigators of SHARP, from the Oxford University Clinical Trial Service Unit (CTSU), Oxford, England. For full results please visit here.

"This is an important study," said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. "Patients with CKD have a high risk of ischemic vascular disease and increased rates of heart attack, stroke, other cardiovascular events and revascularisation procedures. In SHARP, the investigational use of 'Inegy' significantly reduced the risk of these events in a spectrum of patients with chronic kidney disease -- and this was the first demonstration that an LDL-cholesterol lowering medicine could do so."

'Inegy' is not indicated to reduce major vascular events or atherosclerotic events in patients with chronic kidney disease. MSD plans to seek regulatory approvals for the use of ezetimibe/simvastatin in patients with CKD based on the results from the SHARP study. The drug is currently indicated as adjunctive therapy to diet for the reduction of LDL cholesterol in patients with primary hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate.

SHARP is the largest prospective study of LDL-lowering in patients with CKD

SHARP is the largest clinical trial of ezetimibe/simvastatin 10/20 mg conducted to date, and enrolled a total of 9,438 patients under the care of a nephrologist for chronic kidney disease. One-third of patients were undergoing dialysis therapy for end-stage kidney disease at the time of entry, and the remaining patients were pre-dialysis patients with advanced CKD with an average estimated glomerular filtration rate (a measure of kidney function) of 26.5 ml/min/1.73m2. Patients with a prior history of myocardial infarction or a revascularisation procedure were excluded from the study. At randomisation, the average LDL cholesterol of all patients enrolled in SHARP was 2.79 mmol/l.

Patients were initially randomised in a ratio of 4:4:1 to receive ezetimibe/simvastatin 10/20 mg daily versus placebo versus simvastatin 20 mg alone. After one year, patients initially allocated to simvastatin alone were re-randomised to either ezetimibe/simvastatin 10/20 mg daily or placebo for the remainder of the study period. Patients were followed for a median of 4.9 years.

The protocol-specified primary endpoint for the study was the incidence of first major vascular events, defined as the composite of non-fatal heart attack or cardiac death, stroke or revascularisation procedure in the two groups randomised to ezetimibe/simvastatin or placebo at study initiation. (This analysis did not include patients initially randomised to simvastatin alone for the first year.) In the intention-to-treat analysis, ezetimibe/simvastatin reduced first major vascular events by 16.0 percent compared to placebo (p=0.0012). In the group that received ezetimibe/simvastatin (n=4,193) 15.3 percent of patients had a major vascular event, compared to 17.9 percent of patients taking placebo (n=4,191).

In addition, in the full study population of patients, including patients who took simvastatin alone for the first year and were then re-randomised to either ezetimibe/simvastatin or placebo, ezetimibe/simvastatin reduced first major vascular events by 15.3 percent compared to placebo (p=0.0012). The rate of major vascular events in patients taking ezetimibe/simvastatin (n=4,650) was 15.1 percent, compared to 17.6 percent of patients taking placebo (n=4,620).

Results on Major Atherosclerotic Events Also Presented

Based on information from clinical studies of other LDL-lowering medicines that became available after the original SHARP study protocol was implemented in 2003 and before the study ended, the independent SHARP Steering Committee determined that the most relevant "key outcome" for the study should be the incidence of first "major atherosclerotic events." Major atherosclerotic events were defined as the combination of non-fatal heart attack, coronary death, ischemic stroke or any revascularisation procedure; this analysis excluded non-coronary cardiac death and hemorrhagic stroke from the protocol-specified primary endpoint of major vascular events. (The Steering Committee's rationale and statistical analysis plan are discussed in a paper published on-line in the American Heart Journal3). In the intention-to-treat analysis, ezetimibe/simvastatin also reduced first major atherosclerotic events by 16.5 percent compared to placebo (p=0.0022). The rate of first major atherosclerotic events in patients taking ezetimibe/simvastatin (n=4,650) was 11.3 percent, compared to 13.4 percent in patients taking placebo (n=4,620).

In the first year of the trial, ezetimibe/simvastatin 10/20 mg lowered LDL cholesterol by 40 percent compared to placebo, while simvastatin 20 mg lowered LDL cholesterol by 28 percent versus placebo; the reduction achieved by ezetimibe/simvastatin was 30 percent greater than that achieved by simvastatin alone. After two and half years of treatment, which was approximately mid-way through the study, ezetimibe/simvastatin lowered LDL cholesterol by 0.83 mmol/l (32 mg/dL), or 30 percent from baseline, compared to placebo.

The University of Oxford CTSU researchers noted that the reduction in major vascular events and major atherosclerotic events based on the LDL-cholesterol reduction achieved with ezetimibe/simvastatin in SHARP was consistent with reduction of outcomes that would be predicted based on the recently published Cholesterol Treatment Trialists' (CTT) meta-analysis of large-scale statin trials. The CTT analysis, published online in The Lancet, examined the relationship between LDL-cholesterol lowering and reduced rates of cardiovascular events.

One of the secondary endpoints for SHARP was the progression to end-stage renal disease (ESRD) among patients who were not yet on dialysis at the start of the study. A patient was considered to have progressed to ESRD if they started long-term dialysis or proceeded to kidney transplantation following randomisation. On this endpoint, there was no difference between ezetimibe/simvastatin and placebo; 33.9 percent (n=3,117) compared to 34.6 percent (n=3,130) respectively proceeded to ESRD,.1L

Ezetimibe/simvastatin 10/20 mg Tolerability Over the Nearly Five Years of Follow-up

In terms of assessing safety in SHARP, the researchers assessed reports of serious adverse events as well as adverse events that were pre-specified: cancer, myopathy with levels of creatine phosphokinase (CK) >10 x but ≤40 x upper limit of normal (ULN), and reports of myopathy with CK >40 x ULN, hepatitis, persistently elevated liver enzymes (ALT/AST >3 x ULN), complications of gallstones, other hospitalisations for gallstones, and pancreatitis without gallstones.3

Overall, the safety profile of ezetimibe/simvastatin 10/20 mg in this study was consistent with the profile described in the current approved summary of product characteristics.

Ezetimibe/simvastatin (n=4,650) was comparable to placebo (n=4,620) in the incidence of cancer and cancer-related deaths: cancer was reported in 9.4 percent versus 9.5 percent respectively (p=0.89); mortality due to cancer was reported in 3.2 percent versus 2.8 percent respectively (p=0.20).

For other safety analyses that were pre-specified, ezetimibe/simvastatin was also comparable to placebo in the incidence of CK > 10 x but ≤ 40 x ULN (0.4 percent versus 0.3 percent respectively), CK >40 x ULN (0.1 percent in each group), hepatitis (0.5 percent versus 0.4 percent respectively), persistently elevated ALT/AST>3 x ULN (0.6 percent in each group), complications of gallstones (1.8 percent versus 1.6 percent respectively), other hospitalisations for gallstones (0.5 percent versus 0.6 percent respectively) and pancreatitis without gallstones (0.3 percent versus 0.4 percent respectively).

"Merck is proud to support clinical trials such as SHARP and we thank the Oxford University and the thousands of patients and health care professionals who participated in SHARP for their contributions to this study to address this important medical question for patients with CKD," Kim said

1. 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. American Society of Nephrology Conference, Denver, November 2010

2. Summary of Product Characteristics, 'Inegy'

3. 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, American Heart Journal (Available online September 20, 2010 here.)

Source:
MSD