Ezetimibe Fails to Garner Support for CV- Event Reduction Claim From FDA Advisory Committee

A US Food and Drug Administration (FDA) advisory committee voted yesterday against approving a claim that adding ezetimibe, marketed as Zetia by Merck/Schering-Plough, to statin therapy reduces the risk of cardiovascular (CV) events in ACS patients. 

In total, 10 members from the Endocrinologic and Metabolic Drugs Advisory Committee felt the safety and efficacy data from a large morbidity and mortality trial, IMPROVE-IT, did not support the expanded indication for CV event reduction compared with just 5 members who voted for the expanded indication.

The panel voted against the CV-event reduction claim for ezetimibe despite positive data from the 18,000-patient study. During 7 years of follow-up, adding ezetimibe to simvastatin 40 mg significantly reduced the primary composite endpoint—CV death, MI, unstable angina requiring rehospitalization, coronary revascularization, or stroke—by 6.4% when compared with patients who received simvastatin alone. The reduction was driven by a statistically significant reduction in the risk of MI and ischemic stroke. There was no impact on all-cause mortality. 

The absolute reduction in the primary endpoint was just 2.0%, which many of the FDA committee members considered modest, if not “weak.” The advisory committee members agreed the trial met the statistical definition of significant, but many questioned the real-world applicability of the results. On the whole, they simply did not feel ezetimibe added to statin therapy provided patients with “substantial benefit.”

Sanjay Kaul, MD, of Cedars-Sinai Medical Center (Los Angeles, CA), who voted no on the expanded claim, said the modest treatment effect simply was not persuasive enough from a regulatory standpoint to justify the expanded indication. “I am struggling with the clinical meaningfulness of the treatment effect,” said Kaul.

Another who voted no on the expanded claim, John Teerlink, MD, of San Francisco Veterans Affairs Medical Center, said the magnitude of treatment effect was small and the overall results lacked robustness. Like other members of the advisory committee, Teerlink pointed out that the addition of ezetimibe had no effect on mortality.

“I think it’s important for us to acknowledge the success of our therapies at reducing mortality,” said Teerlink. “This is a success story, the fact that it’s hard to show benefit in terms of mortality. It shows we’ve been doing something successfully. That’s good. The challenge is when you don’t see any difference there. I think it’s appropriate to see where the differences are coming from and whether those differences are important or not. It is important to meaningfully reduce myocardial infarctions and strokes, but the absence of any of the larger outcomes remains concerning to me.”

Over the long follow-up period, especially in a group of patients selected because of their high baseline risk, Teerlink said he would have expected to see a reduction in mortality.

Safety, Efficacy in IMPROVE-IT

Ezetimibe was approved by the FDA in 2002 as an adjunct to diet for lowering cholesterol levels in patients with hypercholesterolemia. Unlike statin therapy, however, ezetimibe lacked hard clinical outcomes data, leading many to question its use. In fact, the 2013 American College of Cardiology/American Heart Association cholesterol guidelines are explicit in stating statins should be the first-line treatment for preventing primary and secondary CV events.

The drug also had a long and somewhat troubled history, with data from ENHANCE, a surrogate endpoint study measuring subclinical atherosclerosis using carotid intima-media thickness (IMT), suggesting no effect on atherosclerosis when patients received ezetimibe on top of statin therapy. This led to early speculation that ezetimibe might lower LDL cholesterol but have no meaningful effect on hard clinical events. There were also early questions about whether ezetimibe increased the risk of cancer, a concern dispelled in 2009 by an FDA review.

During the day-long FDA advisory discussion, committee members were mostly satisfied that the drug was safe, although the group was divided as to the “weight” of a numerically higher but not statistically significant rate of hemorrhagic stroke with ezetimibe in IMPROVE-IT.  

All in Favor—or Not

Michael Blaha, MD, of Johns Hopkins Hospital (Baltimore, MD), voted for the CV-event reduction label claim, saying he believes there is a modest unmet need for LDL-lowering add-on therapy in CAD patients. “This is an important space we’re talking about, where clinicians have a hard time treating patients to low LDL cholesterol levels because of statin intolerance or other reasons,” he said.  “In my view, we’ve waited a long time for evidence that a drug added onto a statin works, and we have it [in IMPROVE-IT.] This drug lowered the primary endpoint when added on top of a statin, and that’s the first time we’ve seen that. That’s clinically relevant.”

Another who advocated for the expanded claim was Brendan Everett, MD, Brigham and Women’s Hospital (Boston, MA), saying the IMPROVE-IT trial is the best evidence to date. “It's just not possible to do a perfect trial to get the perfect answer to the clinical question,” he observed. “From my standpoint, this does represent substantial evidence to support approval."

Peter Wilson, MD, Atlanta VA Medical Center (Atlanta, GA), who voted yes for the expanded claim, had high praise for the pivotal trial, saying the “high-quality” study was larger and longer in duration than those the advisory committee typically reviews. Regarding the modest treatment effect, he noted that investigators had a high bar to clear given the low baseline LDL cholesterol levels of the ACS patients in the trial.

On the other side, Milton Packer, MD, of Baylor University Medical Center (Dallas, TX), voted no for the expanded claim but noted that ezetimibe remains on the market and continues to be an option for clinicians looking to lower LDL cholesterol in their patients.

“Everyone who wants to use this drug for risk reduction in cardiovascular disease can do that right now based on the current label,” said Packer. If you believe in the LDL hypothesis, “you have the label for this drug to use for cholesterol lowering,” he said. “If you believe that lowering cholesterol lowers cardiovascular risk, and IMPROVE-IT supports that, you don’t need a label change…You don’t need any additional help from this committee.

Packer praised the IMPROVE-IT investigators, saying the trial was difficult to undertake and sustain and explained that his doubts are based solely on the effect size, and not on the conduct of the trial or the investigators’ efforts.

“You blink and you miss it,” said Packer, referring to the treatment effect.

More critically, Packer questioned whether the modest result could even be replicated. If the IMPROVE-IT investigators were tasked with doing the trial again, he asked, and they ran the trial the same way, would they observe the same benefit with ezetimibe? “I just don’t know,” said Packer. “It’s a coin toss. I just don’t know if we’d see it again. And that’s what gives me pause.”

Understanding the Results

During the day-long meeting, panel members grappled with missing data—primary-endpoint data was available for just 91% of patients in the trial—as well as Merck’s proposal that the results from IMPROVE-IT, which included recent ACS patients, could be extrapolated to other patients, such as those with coronary heart disease. Ultimately, the group felt such an extrapolation was “overreaching,” noting the limited effect seen in ACS patients might be attenuated further in stable patients. 

Also discussed and debated was a subgroup analysis showing the benefit of treatment with ezetimibe in diabetic patients, but not in nondiabetic subjects, and in patients > 75 years but not in younger patients.

Committee members cautioned that subgroup analyses could be “treacherous” and “hazardous” and concluded that these data did not influence their decision to vote yes or no on the expanded label.   

The FDA is not required to follow the advice of the advisory committee although it usually does. 

Source:
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med.2015;372:2387-2397.

Related Stories:

• Ezetimibe Proves Clinical Benefit on Top of Statin Therapy
• IMPROVE-IT Published: Hotly Debated Ezetimibe Helpful When Added to Statin Therapy
• Ezetimibe Benefits Diabetics, and Does Not Increase Risk of New-Onset Diabetes