Icosapent Ethyl Could Prevent Thousands of CVD Events if Used as Indicated

Citing physician awareness as the biggest barrier to use, experts also point to burdensome insurance paperwork and high co-pays.

Icosapent Ethyl Could Prevent Thousands of CVD Events if Used as Indicated

If prescribed to every US adult who has known cardiovascular disease or diabetes with well-controlled LDL cholesterol on statin therapy but elevated fasting triglycerides, icosapent ethyl (Vascepa; Amarin) holds the potential to prevent at least 70,000 cardiovascular events annually, according to extrapolated registry data.

Moreover, the prescription-grade omega-3 fatty acid drug could thwart up to 50% more events if including all adults who would be eligible for a prescription based on Food and Drug Administration approval criteria, which don’t require a specific LDL-cholesterol threshold.

The findings are in line with what was observed in the randomized REDUCE-IT trial, which showed a 25% reduction in major adverse cardiovascular events with no safety issues among a cohort of more than 8,000 statin-treated adults with elevated triglyceride levels and at least one cardiovascular risk factor.

“What our study shows is that in the several million US adults that would fit either the entry criteria from the REDUCE-IT trial or the FDA indications for this product, we can annually prevent many tens of thousands of cardiovascular events,” lead author Nathan D. Wong, PhD, MPH (University of California, Irvine), told TCTMD. “This can of course save many millions of dollars of healthcare costs.”

We can annually prevent many tens of thousands of cardiovascular events. Nathan Wong

Commenting on the findings for TCTMD, Christopher Cannon, MD (Brigham and Women’s Hospital, Boston, MA), said the researchers were conservative in their approach and suggested the number of events that icosapent ethyl could prevent is likely double or even triple that which was observed. “This type of analysis is helpful to wake us all up and say: ‘Look there's this amazing trial, new therapy, and it could save tons of events including cardiovascular deaths if only we would apply the results,’” he said. “It just points out how poor we and our system are at identifying people for good therapies.”

Many Preventable Events

For the study, published online August 15, 2020, ahead of print in the American Journal of Cardiology, the researchers identified all adults aged 20 years and older from the National Health and Nutrition Examination Survey (NHANES) between 1999-2016 who met eligibility criteria for the REDUCE-IT trial. Namely, they had to have known cardiovascular disease or diabetes plus one additional risk factor and have fasting triglycerides of 135-499 mg/dL, hemoglobin A1c < 10%, blood pressure < 200/100 mmHg, and be on statin treatment with LDL cholesterol between 40-99 mg/dL.

In total, they included 319 individuals who represented a sample-weighted population of 3 million adults; 63% had prior CVD (secondary prevention) and 37% had diabetes plus at least one additional risk factor (primary prevention).

Based on REDUCE-IT findings and with the prescription of icosapent ethyl for 4.9 years, the researchers estimated 71,391 primary and 31,660 secondary atherosclerotic CVD events could be prevented annually. Using the modified FDA inclusion criteria, which resulted in 476 individuals representing a population of 4.6 million adults, they estimated the prevention of 60,544 primary and 41,915 secondary events each year.

Preventable Events


REDUCE-IT Inclusion Criteria

FDA Eligibility Criteria

Primary Composite Events








Secondary Composite Events








CV Death or Nonfatal MI


Fatal or Nonfatal MI



Urgent or Emergent Revascularization


CV Death



Wong pointed to lack of physician awareness as the biggest current barrier to the appropriate patients being prescribed icosapent ethyl. “This is of course a branded medication that recently, less than a year ago, got FDA approval for cardiovascular event reduction,” he said. “For many clinicians, including cardiologists and especially interventional cardiologists, icosapent ethyl may not yet be on their radar screen as an important additional therapy that should be considered to be prescribed along with a high-intensity statin in our high-risk patients, given it provides an additional 25-30% reduction in subsequent cardiovascular events beyond statin therapy.”

In addition to more education for healthcare providers, Wong said “systems approaches, such as reminders in electronic medical record systems” could be helpful in increasing prescriptions of high-intensity statins and other evidence-based therapies, including icosapent ethyl, in the appropriate patient populations to maximize opportunities for prevention of subsequent cardiovascular events.

Lastly, he highlighted the fact that the American College of Cardiology/American Heart Association cholesterol guidelines do not yet include any recommendation for icosapent ethyl as they were last updated at the same time the REDUCE-IT trial data were presented. “A further update to our US cholesterol management guidelines would be indicated to consider the value of this important therapy in patients with established atherosclerotic cardiovascular disease as well as diabetes and multiple risk factors who are already on statins given that icosapent ethyl provides further incremental, added risk-reduction benefit,” Wong said.

Current European Society of Cardiology and American Diabetes Association guidelines have already been updated to include icosapent ethyl.

Barriers to Use

For his part, Cannon acknowledged that limited physician knowledge is a big factor in why more patients have yet to be prescribed icosapent ethyl. However, he added, “there are lots of barriers. Reminding physicians and simply awareness of the data is certainly the first step, and that used to be the basic one. But then in a busy clinic you have to have time to remember that this could be an intervention. . . . I think it kind of just gets lost in the shuffle of other things in healthcare that this has not been beaten into us.”

Additionally, insurance coverage can also factor into why patients don’t get this drug. “We have gotten sucker punched with PCSK9s and just about every other new medicine where you have to fill out a prior authorization half the time to get it,” Cannon said, adding that this paperwork can pose a barrier. “Then, once you get approval, there's the co-pay business. If you have a non-Medicare patient, then you have to remember to get the co-pay card from the company and make sure it works.”

No one wants to take a statin, but if they hear it's purified fish oil, the patients don't resist. Christopher Cannon

Cannon cited an example of one of his patients discovering a $430 co-pay for icosapent ethyl, not telling him, and therefore not taking the drug for over a year.

On the other hand, unlike with statins where patients are often hesitant to try, he said there is less of a phobia with this drug. “No one wants to take a statin, but if they hear it's purified fish oil, the patients don't resist. They're like, ‘Okay doc, no problem.’ So that's one barrier that doesn't exist, which is a big one actually,” he observed.

Overall, Cannon said that “all the patients that I've started [on this drug] have been very happy with it and like the idea of the protection. There are no muscle aches. So, it's gone smoothly for me clinically.”

He would like to see future research delve into its use in primary prevention. “The last one that was done was VITAL—[in] 25,000 patients the 1-g dose didn't really do much, but that could be a nice follow-up to say should everybody be getting this,” Cannon said. “It's got very few side effects—not none, there is the A-fib and bleeding that were seen in the trial—but this would potentially be something that could go even more broadly.”

Additionally, both Cannon and Wong said that further studies should look at the mechanism of action of icosapent ethyl. “We know that the main reason for this drug's benefit is probably not due to its reduction of triglyceride levels, but there does seem to be evidence that this product may benefit patients because of its antioxidant and anti-inflammatory activity,” Wong said. “These and other actions need to be further elucidated to understand the main mechanisms responsible for the drug's benefit.”

  • This study was presented in part at the American College of Cardiology Scientific Sessions, March 2020 and was funded by a contract to the University of California, Irvine from Amarin Pharma.
  • Wong reports research support through the University of California, Irvine from Amarin, Amgen, Novartis, Boehringer-Ingelheim, Gilead and Novo-Nordisk and is on the speakers bureau for Amarin and Esperion.
  • Cannon reports receiving research grants from Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Pfizer and consulting fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer-Ingelheim, Bristol-Myers Squibb, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, Rhoshan, and Sanofi.

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