June 12th, 2011
CardioExchange Panel: Ezetimibe + Simvastatin for Chronic Kidney Disease — What’s the Point of SHARP?
Last week saw the publication of the SHARP trial (Study of Heart and Renal Protection) in which some 9,200 patients with chronic kidney disease (CKD) were randomized to either placebo or the combination of simvastatin and ezetimibe.
CardioExchange put questions about these data to a panel of experts. Whose views do you agree with? What points did our panelists miss?
See a similar panel’s reactions to the FDA warning on high-dose simvastatin here.
Does the SHARP trial tell us anything about the value of adding ezetimibe to statin therapy? And would you derive any recommendations for the treatment of patients with advanced kidney disease from this study?
While ezetimibe was part of the active drug strategy, it is not possible from these data to assess the independent contribution of the drug to the combination strategy. What we did learn is that an LDL lowering strategy with these two drugs in this group of patients is better than placebo. The incremental value of ezetimibe when added to simvastatin (compared with the statin alone) is being tested in the ongoing IMPROVE IT trial. For full disclosure, our research group (DCRI) along with the TIMI study group are leading the IMPROVE IT trial.
SHARP contributes to our clinical decision-making knowledge base given that there was still uncertainty as to the incremental benefit of lipid-lowering therapy in patients with CKD. Lipid-lowering therapy, specifically LDL lowering, in patients with CKD reduces the risk of cardiac events. The magnitude of this effect is consistent with other data in patients without CKD and with comparable levels of LDL lowering. While it is likely, even probable, that the magnitude of LDL lowering is what confers the clinical benefit, the most evidence-based conclusion (and hence the recommendation) is that treatment with this combination in patients with CKD results in a reduction in cardiac events. It’s tempting to state that any strategy that lowers LDL to a similar degree is sufficient to confer the clinical benefit seen in this population, but we can only comment on what was tested in the trial. In addition to the efficacy statement, the combination strategy appeared safe in this population as studied.
This study tells us nothing about the efficacy of adding ezetimibe to stain therapy. It is entirely plausible that the observed benefits were due solely to simvastatin. Furthermore, the primary endpoint was not appropriate, mixing soft events, such as revascularization, with irrevocable events such as death and MI. There was no benefit shown for MI plus CHD death.
I would not use simvastatin plus ezetimibe to treat advanced kidney disease patients based upon this trial. In such patients, evidence-based use of statins is prudent using the current guidelines for drug administration to patients at high risk for CHD.
This trial had an unfortunate design which provides no information on the value of ezetimibe. The trial should have included a statin monotherapy arm. Beyond this, the overall trial result was disappointing with no significant effect on the important endpoints of non-fatal MI or CHD death. Even if one accepts the investigators’ change in the study endpoint during the trial to a broader composite endpoint of “any major atherosclerotic event” (consisting of coronary events, strokes, and revascularization procedures) the NNT was a disappointing 48 over 4.9 years (1 event per 235 patient-years of treatment), driven primarily by revascularizations. This provides no compelling justification either on an efficacy, or likely a cost-efficacy basis, for use of a branded simvastatin/ezetimibe combination product, over statin monotherapy.
We should be careful not to generalize these results obtained with a specific drug to the overall treatment of lipid disorders in kidney disease. But, in the broad sense, the literature remains unclear whether a disease modifying approach with lipid lowering therapy is truly effective in chronic kidney disease.
SHARP doesn’t really tell us much about ezitimibe. It was not specifically designed to evaluate the incremental effect of add-on ezetimibe therapy to patients optimally treated with statins. Without an active control statin treatment arm, it is not possible to ascertain the relative contribution of ezetimibe on the overall treatment effect. What one can take away from this trial is that LDL lowering of about 33mg/dL (from a baseline level of about 108 mg/dL) achieved with a low fixed-dose of simvastatin in combination with ezetimibe is associated with a modest 2.1% absolute (0.4% per year) or 17% proportional reduction in major atherosclerotic events. To claim these as BIG BENEFITS (as stated in the press release from CTSU) is simply a case of “over-egging the pudding”. The treatment benefit was driven by reduction in revascularization (the most prevalent, but arguably the least clinically important endpoint) and non-hemorrhagic stroke, without significant benefit in coronary death or nonfatal MI. There were numerically higher, but not statistically significant, number of all cause deaths and cancer-related deaths in the active treatment arm, and the main renal endpoint (progression to ESRD) was not significantly different.
If one is hesitant to use high-dose statins in advanced or end-stage renal disease patients because of heightened risk of muscle- or liver-related adverse events, then this trial provides some reassurance that a low, fixed-dose statin, in combination with ezetimibe might be an effective and safe alternative. However, one could argue that similar reduction in LDL levels and secondary “atherosclerotic outcomes” were observed with 20 mg atrovastatin alone in 4D trial (the primary results failed to yield overall treatment benefit in 4D) which enrolled a much higher-risk patient population as reflected in a nearly 5-fold greater risk of vascular mortality per year. Bottom line, without a direct head-to-head comparison trial, one cannot draw definitive conclusions about the comparative effectiveness and safety of low, fixed-dose statin plus ezetimibe versus higher-dose statin alone in patients with advanced kidney disease.
Simvastatin is a good drug, but atorvastatin showed the same benefits in the The German Diabetes and Dialysis Study (4D) trial. SHARP tells us nothing about ezetimibe.
This study does not answer the question of whether or not they would have gotten the same result if they used simvastatin alone (ie, if ezetimibe had anything to do with the observed results) or if ezetimibe is safe. But, it is notch on the belt in favor of the drug, because it is a RCT that used ezetimibe and reduced events.
The 4D trial showed significant reductions in “all cardiac events” with atorva 20 mg daily – so it is an overstatement to say that they are “first and only prospective clinical study in patients with chronic kidney disease” to reduce atherosclerosis-related cardiac events as they did in their press release. The paper refined that to say “two trials of statin therapy “had not detected significant benefits in their primary outcomes.” True enough, but not very compelling since the SHARP investigators changed their primary endpoint to essentially the secondary endpoint in 4D. Indeed, the secondary endpoint in 4D (“all cardiac events”) was essentially the primary endpoint in SHARP. Atorvastatin had a similar relative benefit (18%) but a greater absolute difference (6% vs 2%). The p value was higher because the study was a lot smaller) Rosuva 20 mg in AURORA did not show a benefit, but AURORA and 4D subjects were very different than those in SHARP. All were on dialysis. Only 1/3 of SHARP were, so they had less advanced kidney disease and were less likely to die of dialysis-related problems (including cardiac) and more likely to die of atherosclerosis complications. The differences lie in the study populations, causes of death, degree of kidney disease. Also, we already knew that those with GFR from 30-60 had CVD reductions from the pravastatin meta-analysis, so this result is completely expected. I think patients with advanced kidney disease will benefit from statin therapy, if their life expectancy is long enough to see benefits. The magnitude of the benefit probably is lower once they are on dialysis, but it is important when people have advanced but not dialysis-dependent CKD.