November 22, 2010 (Denver, Colorado) — Final results of the Study of Heart and Renal Protection (SHARP) show that cholesterol lowering with a combination of simvastatin and ezetimibe (Vytorin, Merck) in patients with kidney disease significantly reduced the risk of "major atherosclerotic events" by 17% and the primary end point for the study, major vascular events, by almost the same degree.
|Dr Colin Baigent [Source: Clinical Trials Service Unit]|
Lead investigators Drs Colin Baigent and Martin Landray (Clinical Trials Service Unit, Oxford, UK) presented the results today here at the American Society of Nephrology Renal Week 2010.
After a median follow-up of 4.9 years, patients randomized to the ezetimibe/simvastatin combination experienced a 17% reduction in major atherosclerotic events compared with the placebo group, a statistically significant difference (p=0.0022).
For the prespecified primary end point of major vascular events, patients in the active-treatment group experienced a statistically significant 15.3% reduction (p=0.0012), as compared with placebo.
According to trial investigator Dr Adeera Levin (University of British Columbia, Vancouver), the results should change practice, by providing a clear answer to physicians, who have "been all over the map."
"Variability in practice was huge, and there was a lot of misunderstanding. Everyone worried these drugs might be unsafe [in chronic kidney disease patients] and that they didn't work. Now what SHARP says is, these drugs are safe and they work."
Controversial Trial Tweaks
The similar findings for both "atherosclerotic" and "major vascular events" may help put to rest controversy that has dogged this study in advance of its presentation, namely the announcement by investigators that they would not be "emphasizing" the prespecified primary end point of major vascular events when presenting the final results, as reported by heartwire . That decision was taken after the trial sponsors rejected a request to formally change the trial's primary end point--something that would surely have opened the credibility of the trial results to major scrutiny had the "new" end point proved positive and the prespecified had not.
The SHARP steering committee's stated reason for changing its "emphasis" was to reduce the possibility of a false-negative trial, where the potential benefit of LDL-lowering therapy on atherosclerotic outcomes in patients with chronic kidney disease was diluted by nonatherosclerotic events. As designed, the SHARP trial's primary end point had included hemorrhagic stroke, which is unlikely to be altered by LDL lowering, Baigent explained to heartwire last month. "We wanted an end point that would be as sensitive as possible to any real benefit, which is reflected in nonfatal myocardial infarction and coronary cardiac death, revascularization, and ischemic stroke," he said.
Details on the changes, as well as some early safety and efficacy data, were published online September 20, 2010 in the American Heart Journal .
Commenting on the changed end-point "focus" for heartwire , Levin called it a wise and "clever" decision.
The SHARP trial was launched before the results of other ongoing trials clarified what might be expected of the drug in kidney-disease patients. "This is a drug that affects atherosclerotic disease; this isn't a drug that's going to let you live forever. So let's make an end point that's directly related to the action of the drug," she said. "Don't forget, the [SHARP steering committee] made this decision while they were still blinded, before the study was closed; they did it publicly and against what the sponsor wanted them to do. The sponsor wanted them to keep the original end point, but what they did is stick to their guns. It was very brave of them, and very smart."
SHARP enrolled 9438 patients with chronic kidney disease either on dialysis or with a creatinine level of >1.7 mg/dL for men or >1.5 mg/dL for women, all with no history of MI or coronary revascularization. As Baigent observed in presenting the results, the main entry criteria had to be that a patient's doctor was uncertain whether or not the patient should be on cholesterol-lowering drugs: previous studies of LDL-lowering in chronic kidney disease patients have been "inconclusive," he noted.
In the first year of the study, patients were randomized to either ezetimibe/simvastatin (10 mg/20 mg) or placebo, with an additional 1000 patients randomized to simvastatin alone. After one year, patients in the simvastatin-alone arm were rerandomized, so that the comparison presented today was the outcomes in patients randomized to placebo vs ezetimibe/simvastatin.
As noted, both major atherosclerotic events and major vascular events were reduced in the active-treatment group after almost five years of treatment.
For the secondary end point of progression to end-stage renal disease, no differences were seen between groups, with roughly one-third of patients in both arms progressing to dialysis or transplantation. Subgroup analyses, including an analysis of patients on or off dialysis, found no difference between groups.
Importantly, said Baigent and Landray, no difference in incidence of cancer was seen between groups, at roughly 9.5% in both. Other safety end points, including rates of myopathy, hepatitis, gallstones, etc, were no different between groups.
Of note, one-third of SHARP patients discontinued treatment over the course of the trial, with similar rates of "noncompliance," as investigators put it, between groups. According to investigators, this implies the results would actually be even stronger in the real world, where patients and physicians could be confident that taking their meds would actually be beneficial.
"Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30 to 40 events per 1000 patients treated for five years," they estimated.
Commenting on the study for heartwire , Dr James Stein (University of Wisconsin, Madison) pointed out that while SHARP is being touted as the first trial to show a benefit of cholesterol lowering in chronic kidney disease patients, it is not. The Deutsche Diabetes Dialyse Studie (4D) also showed significant reductions in stroke and all cardiac events with a statin only (atorvastatin 20 mg), although the end point of all cardiac events was secondary, not primary, in 4D.
Of note, 4D found opposite results from A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), which saw no benefit of cholesterol lowering in chronic kidney disease patients, fostering confusion over the question of lipid-lowering in such patients.
"I think most kidney docs were still treating patients with statins despite the AURORA study, and this just proves to them that they were right after all," Stein told heartwire . "I would point out that the absolute benefits [in SHARP] were quite small--you have to treat a lot of people to prevent one event. But most of these patients are already being treated with statins, and this is going to help cement that."
Answers and More Questions
But for Stein, at least two questions are not answered in SHARP. For one, he says, he is not reassured on the ezetimibe cancer findings--an issue debated in the past. "This is a small and short study. . . . This just doesn't tell us anything about cancer: a five-year study in people with advanced kidney disease is not a place to study the cancer safety of a drug."
As well, he says, SHARP does not speak to the role of ezetimibe on top of a statin. "This tells us really nothing at all about the efficacy of ezetimibe and whether ezetimibe had anything to do with the results. It's perfectly possible that they would have gotten the same results if they'd used simvastatin 20 mg or simvastatin 40 mg a day." To understand the role of ezetimibe, SHARP would also have needed a statin-only arm--something SHARP had only for the first year of the study.
But Levin points out that by design, SHARP set out specifically to use a low, fixed-dose statin, in combination with ezetimibe, in order to avoid what many thought would be a heightened risk of myositis and liver abnormalities in chronic kidney disease patients, something ultimately not seen in SHARP.
"By using ezetimibe and a fixed-dose, relatively low-dose statin and showing that you could lower lipids safely and effectively and get positive effects, I would say that this [combination] possibly allowed you to not have those side effects," she speculated. "And it's at least conceivable that you might have seen more side effects with higher statin doses."
Baigent also addressed the specific role of ezetimibe and the lack of a statin-only arm in a morning press conference, noting that the three-way randomization in the first year was to make sure ezetimibe was safe--something not well known at the study outset. And he pointed out that to continue the three-way randomization would have required a sample size of 30 000 to 40 000 participants. "We struggled to recruit 9000, so you can imagine how hard it would have been to recruit 40 000."
And Baigent pointed out that the amount of LDL lowering seen in SHARP and the reduction in events it produced were similar to that seen for other trials that have used statins alone. "So my guess is that no, it's not something special that ezetimibe is doing, just lowering LDL cholesterol the same way that statins do."
But he also thought the questions about ezetimibe's contributions were somewhat beside the point. "We thought the key question was, does a large reduction in LDL cholesterol benefit kidney patients? This trial shows very clearly that it does."
SHARP was funded by Merck and by Schering Plough (which merged in 2009), with additional support from the Australian National Health and Medical Research Council, the British Heart Foundation, and the UK Medical Research Council. Baigent has previously disclosed having no personal conflicts of interest. Levin has disclosed serving on the medical advisory board of Amgen Canada and Amgen USA, as well as Janssen Cilag International, Ortho Biotech Canada, and Roche International. She has received grants from the Kidney Foundation of Canada to study comorbidities associated with chronic kidney disease and more recently to study the variability of the care delivered across Canada to patients with chronic kidney disease. She has also received grants from BC Health Research Foundation, BC Transplant Foundation, Janssen Cilag International, Ortho Biotech, Amgen, and Genzyme. Stein disclosed serving on data safety and monitoring committees for clinical trials sponsored by Abbott, Lilly, and Takeda.
The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Heartwire from Medscape © 2010
Cite this: SHARP: Ezetimibe/Simvastatin Combo Cuts Atherosclerotic and Vascular Events in Kidney-Disease Patients - Medscape - Nov 22, 2010.