I've written a bit previously in this blog about the evidence around lipid-lowering therapies, and in particular about the lack of evidence for combining other lipid-lowering therapies, including ezetimibe, with statins.
Tomorrow, the FDA will apparently be taking up a request to approve Vytorin (simvastatin/ezetimibe) for the treatment of patients with chronic kidney disease (CKD). As a result of this request for approval, we also have access to the FDA review of data from the SHARP trial.
SHARP was published in Lancet in June of 2011. SHARP was a trial comparing simvastatin/ezetimibe with placebo in nearly 9300 patients with chronic kidney disease. By way of background, it is important to know that two prior trials of statins in patients on dialysis, 4D and AURORA, had failed to find a statistically significant reduction in events with statin therapy. The non-significant point estimates were about an 8% reduction in events in 4D and a 4% reduction in AURORA.
That makes end-stage renal disease (ESRD; essentially, patients requiring chronic dialysis) an unusual condition when it comes to statin therapy. People with ESRD are at very high risk for cardiovascular events, but get little benefit from statins, unlike almost every other high risk group.
Into this comes simvastatin/ezetimibe, a drug without a clear use. Ezetimibe has never been shown to add clinical benefit to treatment with simvastatin, but based on surrogate outcomes the combination drug became widely prescribed until other surrogate outcomes made people concerned that ezetimibe might really be worthless or worse.
Perhaps that made CKD seem like fertile ground for exploring benefits with simvastatin/ezetimibe. The SHARP trial when it was published was promoted as showing unique benefits in CKD including, for the first time, in patients with ESRD.
The abstract says things like:
After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not.
Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
So, based on SHARP, the claim is being made that simvastatin/ezetimibe, unlike statin monotherapies before it, works in patients on dialysis because it reduced events in all patients with CKD, and the effect in the subgroup of patients on dialysis was not statistically significantly different from the effect in those not on dialysis.
Is this a fair argument?
In general, we look askance at claiming that effects in subgroups differ from the overall effect in a randomized trial. While people are always asking "does drug X really work in women? the elderly? blacks?", in reality most interventions work similarly across a broad patient population. So why object to such a standard, and seemingly reasonable argument for simvastatin plus ezetimibe?
There are two interrelated main problems:
The first is that we are not starting from a position of believing that the effect of a statin-based intervention should be the same in patients with and without ESRD. Based on what happened in prior trials of statins that included less severe CKD, where statins seemed to have their usual benefits, and the 4D and AURORA trials where they had much smaller benefits if any, we already knew that the ESRD subgroup was likely important and special.
The second is that the actual results are in no way reassuring that the subgroups were similar, even if they were not statistically significantly different. Among all patients in SHARP, simvastatin/ezetimibe reduced events by 17%. However, in the 6247 patients not on dialysis it reduced events by 22%, and in those on dialysis it reduced events by a non-significant 10%. Those numbers look rather far apart given our a priori concerns, and even if not statistically significantly different from each other, 10% seems reminiscent of 4D and AURORA.
Still, 10% is a larger reduction than the 8% in 4D or the 4% in AURORA, right? Well, only if you look at all the dialysis patients in SHARP. The 4D and AURORA trials only enrolled patients on hemodialysis, while SHARP enrolled patients both on peritoneal dialysis and hemodialysis. In the small number of peritoneal dialysis patients in SHARP there was a non-significant 30% reduction in events, which is what brought down that average number for all dialysis patients. If you looked just at the 2500 hemodialysis patients, the population studied in the earlier trials, the reduction in events was just a non-significant 5%, similar to AURORA and not even as good as 4D.
Given, this, the argument is completely unpersuasive. Failing to show a statistical difference between effects in the dialysis subgroup and the non-dialysis subgroup is just a way of hiding the reality that simvastatin/ezetimibe did not produce clinically significant or statistically significant benefits in patients on hemodialysis.
So what are we left with? I think we can confidently say after SHARP that simvastatin/ezetimibe reduces cardiovascular events in patients with CKD who do not have ESRD, and that this reduction is right in the ballpark of what we would have expected with simvastatin alone. Further, we can note that yet again a statin-based treatment showed little or no benefit in patients on hemodialysis and that there is absolutely nothing in the results from SHARP to suggest that ezetimibe provides some added clinical benefit to simvastatin alone in either patients with earlier stage CKD or patients with ESRD.
As was the case before SHARP, we have no convincing evidence that any lipid-lowering therapy added to a statin improves clinical outcomes in any patient population.