FDA Panel Recommends High-Dose EPA for CV Event Reduction

November 14, 2019

Icosapent ethyl (Vascepa, Amarin) was today unanimously recommended by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee for approval to reduce cardiovascular events as an adjunct to statin therapy in patients with elevated triglyceride levels.

However, the exact population for whom the drug, a high-dose eicosapentaenoic acid (EPA) product, should be prescribed was not decided at today's meeting. All 16 committee members voted for in favor of approval for use in patients with established cardiovascular disease (secondary prevention population), but there was disagreement over whether it should also be indicated for the high-risk primary prevention population, including those patients with diabetes.

The drug is already on the market for the treatment of patients with very high triglyceride levels (over 500 mg/dL).

The new indication discussed at the advisory committee meeting is based on the REDUCE-IT trial, which showed a 25% relative risk reduction in major adverse cardiovascular events with icosapent ethyl vs placebo in patients with triglycerides over 135 mg/dL and who had cardiovascular disease (70% of the study population), or who were high-risk primary prevention patients with diabetes and one additional risk factor (30% of the study population).

The REDUCE-IT trial was first presented at last year's American Heart Association (AHA) Scientific Sessions, and was also published in the New England Journal of Medicine.

Discussions at the FDA Advisory Committee meeting centered around the different risks and benefits in secondary vs primary prevention; the use of mineral oil as the placebo, which may have biased the results by reducing the absorption of statins; and how the two main adverse effects seen with the product — atrial fibrillation and bleeding — should be managed.

Secondary Prevention/High-Risk Primary Prevention

While the study showed an overall significant 25% reduction in major adverse cardiovascular events in the whole study population, the benefit was greater in those patients with established cardiovascular disease (35% relative risk reduction). The high-risk primary prevention population showed a nonsignificant relative risk reduction of 16%. 

Several members of the committee voiced concern about approval for the high-risk primary prevention population considering they comprised just 30% of the study population, and in whom the primary endpoint was not statistically significant when this group was considered separately.

"The benefit in the secondary prevention population in the study is overwhelming and convincing. But the results in the primary prevention population are unconvincing," said committee member James de Lemos, MD.

"It is not clear to me that there is a net benefit in the primary prevention population. I do not think we should reward sponsors for enrolling a small subset of primary prevention patients and then getting a broad indication for which we really don't have enough evidence," added Lemos, a professor of medicine at UT Southwestern Medical Center in Dallas, Texas.

Several committee members took a similar view. Others, however, argued that it was the overall result that was important and it was difficult to consider specific groups separately.

One such committee member was Marvin Konstam, MD, chief physician executive of the Cardiovascular Center at Tufts Medical Center in Boston, Massachusetts.

"I'm inclined not to split the population," he said. "I believe the vast majority of people in this trial would have had cardiovascular disease. If we did endothelial function tests in them we would see that. It's just some hadn't yet had an event. But the FDA does need to look at the net clinical benefit in the lower risk primary prevention population included in the study."

And committee chair Kenneth Burman, MD, director of the Endocrine Section at Medstar Washington Hospital Center, District of Columbia, recommended approval for both secondary and primary prevention, as included in the REDUCE-IT trial.  

He also suggested that the age entry criteria in the study (>45 years for secondary prevention, and >55 for primary prevention) could possibly be expanded. "I wouldn’t want to deny it to patients who fit the other criteria but were 35 or 40."

LDL and Triglyceride Specifications

When asked what other specifications should be included for the approved patient population, the committee mostly agreed that they should be in line with the REDUCE-IT entry criteria, which stipulated an LDL level below 100 mg/dL and triglyceride level above 135 mg/dL.

Although it was originally believed the main benefit of icosapent ethyl would be through lowering of triglycerides, results of REDUCE-IT found similar benefits regardless of baseline or on-treatment triglyceride levels.

In his presentation of the trial to the committee, lead investigator Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, concluded, "The only analysis that has correlated any biomarker with outcome is the one for on-treatment EPA levels. I predict it will take years to sort out the exact mechanism of benefit of EPA but the clinical data are clear."

Consumer representative Anna McCollister-Slipp pleaded with the FDA not to be too prescriptive with the label. "The more restrictions imposed, the more difficult it will be for patients to get access. Insurance companies will deny coverage if they can," she said, prompting applause from the audience.

Did Mineral Oil Bias the Results?

Another major talking point at the meeting was the use of mineral oil as the placebo in REDUCE-IT.

Yunzhao Ren, MD, PhD, clinical pharmacology reviewer at the FDA, reported that mineral oil could have interfered with the absorption of statins, which may explain the 10% increase in LDL seen in the placebo group in the REDUCE-IT trial. "This may have biased the results in favor of icosapent ethyl," he suggested.

But Ren added that the LDL difference between the two groups would have only accounted for an approximate 3% increase in cardiovascular risk, which would not outweigh the large reduction in risk seen with icosapent ethyl.   Most committee members seemed to accept this analysis.

Jack A. Yanovski, MD, PhD, chief, Section on Growth and Obesity, National Institutes of Health, said, "I think the mineral oil issue has been adequately addressed. I think it is extremely unlikely that it would have a substantial impact to negate the beneficial results observed with icosapent ethyl."

Atrial Fibrillation/Bleeding Adverse Effects

In terms of side effects, there was much discussion on the increased incidence of atrial fibrillation/flutter and bleeding events seen with icosapent ethyl vs placebo in the REDUCE-IT trial.

FDA clinical reviewer Iffat Nasrin Chowdhury, MD, presented an analysis of the adverse events showing that any bleeding occurred in 11.8% of icosapent ethyl and 9.9% of placebo patients and serious bleeding in 2.7% vs 2.1%, respectively. Fatal bleeding was not increased with icosapent ethyl and was similar between the groups (0.5% vs 0.6%).

The main increase in bleeding was seen in patients also taking antithrombotics; in these patients, any bleed occurred in 12.5% on icosapent ethyl vs 10.4% on placebo.

Atrial fibrillation/flutter requiring hospitalization occurred in 3.1% of icosapent ethyl patients vs 2.1% of placebo patients. The increase in AF was most marked in those patients who already had AF at baseline (12.5% vs 6.3% on placebo).

But Bhatt noted that there was no increase in stroke — the most feared complication of AF — in the icosapent ethyl group; rather, there was a significant reduction in stroke in the active treatment group. 

Most committee members said they thought both the bleeding and AF adverse events were outweighed by the benefits of icosapent ethyl, especially in the secondary prevention group.

"I think we can monitor for both AF and bleeding risk and this can be managed in the labeling, but postmarketing surveillance studies would be helpful to gain more information on these adverse effects," said Elizabeth Chrischilles, PhD, chair of epidemiology at the University of Iowa in Iowa City.

But committee member Konstam was more cautious. "We always have to be aware of risk-benefit and this needs to be addressed clearly, especially in the primary prevention population. There is a possibility of the risk catching up with the benefit in the lower-risk primary prevention population."

During the public hearing part of the meeting, all but one of the speakers (mostly clinicians) urged the committee to recommend broad approval of the product, stressing that icosapent ethyl meets a large unmet need for many patients who have high residual cardiovascular risk despite taking maximal tolerated statins. Several clinicians said they had already tried to prescribe the product since the REDUCE-IT results were published but it had been rejected by insurance companies.

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