Meeting News

Icosapent ethyl appropriate to use to reduce CV risk, despite pending questions

CHICAGO — Findings of cardiovascular benefit with icosapent ethyl treatment from the REDUCE-IT trial have already revealed actionable clinical implications, but determining whether triglyceride reductions or eicosapentaenoic acid increases are the key mechanisms will be the focus of continuing research, according to a speaker at the Cardiometabolic Heath Congress.

Deepak L. Bhatt

“Regarding triglycerides, there is not really too much question anymore that these are indeed a causal risk factor; not just a risk marker but on the pathway to atherosclerosis,” Cardiology Today Editorial Board Member Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, said during a presentation, adding that “there are a number of promising therapies for hypertriglyceridemia,” highlighting the targeting of RNA as “particularly promising.”

In contrast, Bhatt said that low-dose omega-3 mixtures don’t appear to make much of a difference based on the available data, but that hasn’t stopped the use of fish oil supplements.

“I think there’s a lot of use of supplements out there and I would discourage the use of these agents that are ineffective and expensive,” Bhatt said.

REDUCE-IT primary findings

Although the effects of these fatty acids in lower doses are negligible, icosapent ethyl (Vascepa, Amarin Pharmaceuticals) is a “transformational medicine” that, much like penicillin and paclitaxel, is created with naturally occurring elements, according to Bhatt. It was tested for its cardiovascular benefits in the REDUCE-IT trial.

As part of the trial, researchers randomly assigned adults aged at least 45 years with cardiovascular disease and triglycerides of at least 150 mg/dL to either a daily 4 g dose of icosapent ethyl (n = 4,089; mean age, 54 years; 28% women) or placebo (n = 4,090; mean age, 64 years, 29% women). Participants were then followed for roughly 5 years, according to Bhatt, with the researchers evaluating how long it took for participants to experience a major CV event, including CV death, myocardial infarction, stroke, coronary revascularization or unstable angina.

After 5 years, the researchers found that those taking icosapent ethyl were at a lower risk for this primary endpoint compared with those taking placebo (HR = 0.75; 95% CI, 0.68-0.83). In addition, those taking icosapent ethyl were at lower risk for CV death, MI or stroke than those taking placebo (HR = 0.74; 95% CI, 0.65-0.83) and were also at lower risk for multiple events, with total event risk reduced by 30% for those taking icosapent ethyl compared with those taking placebo (RR = 0.7; 95% CI, 0.62-0.78).

Bhatt also noted that most adverse event rates were “virtually identical,” although there was an “imbalance” in serious bleeding events and higher rates of atrial fibrillation for those taking icosapent ethyl compared with those taking placebo.

The foundation for the REDUCE-IT trial is a strong one. Prior to REDUCE-IT, the JELIS and CHERRY trials were a “great one-two punch” in that they revealed that eicosapentaenoic acid may have CV benefits, although Bhatt noted that both studies had limitations in study design. In addition, the MARINE and ANCHOR trials provided more specific building blocks for the REDUCE-IT trial as they examined the safety and efficacy of icosapent ethyl specifically.

Completing the story

While many of the findings of REDUCE-IT are important, Bhatt also highlighted other portions of the data that are worth considering and may provide mechanistic evidence. For example, Bhatt noted that trial data revealed a larger change in numerous biomarkers compared with baseline for those taking icosapent ethyl compared with those taking placebo. In particular, those taking icosapent ethyl had a 19.7% greater reduction in triglycerides (P < .0001) and a 358.8% greater increase in eicosapentaenoic acid (P < .0001) compared with those taking placebo.

“My own feeling is that what really drove the benefit in this trial ... was this large change in levels of [eicosapentaenoic acid],” Bhatt said.

In addition to the benefits shown, the REDUCE-IT trial has also produced more robust results in comparison with other trials aimed at evaluating the reduction of triglycerides, including the JELIS, GISSI-P, HPS2-THRIVE, AIM-HIGH, ACCORD-Lipid and FIELD trials.

A unique aspect of the REDUCE-IT trial was the incorporation of triglyceride variability. Bhatt explained that an average of triglyceride measures taken during screening and those taken after the researchers randomly assigned participants to a regimen was used to set baseline triglycerides. The researchers also created triglyceride tertiles and found “consistent benefits” with icosapent ethyl treatment, although the HR was lowest for those with a baseline triglyceride level of more than 250 mg/dL (HR = 0.68; 95% CI, 0.57-0.8).

“In relative terms, consistent similar benefits statistically across tertiles but in absolute terms, maybe a little bit more bang for your buck as the tertiles go up,” Bhatt said, while adding that when looking at “achieved triglycerides,” there was also consistency in the results.

“Some have said this is evidence that there is a triglyceride-independent benefit of icosapent ethyl, and I happen to agree,” Bhatt said. “I do think triglycerides are part of the story but not the whole story.”

The rest of that story may be found in how eicosapentaenoic acids provide benefits for endothelial dysfunction and oxidative stress, inflammation and plaque growth and unstable plaque as well as in blood pressure reduction, according to Bhatt, who also noted that how eicosapentaenoic acids interact with cellular membranes may play a role. These and other factors will be evaluated in studies currently being conducted, including EVAPORATE, STRENGTH and PROMINENT. Bhatt said the latter two having the potential to shed even more light on REDUCE-IT’s findings.

“There are other trials that will come that will help really determine whether it’s an [eicosapentaenoic acid] story or a triglyceride-lowering story,” Bhatt said. “When these two trials are done, we’ll see is it any omega-3 at a high dose in STRENGTH or is it any triglyceride lowering in PROMINENT that leads to cardiovascular benefit. I think at the end of both these series of trials we’ll know if it’s just an [eicosapentaenoic acid] at 4 g per day story as in REDUCE-IT, or whether it can be generalized.”

With professional organizations such as the American Diabetes Association, American Heart Association and European Medicines Agency incorporating some of the research about icosapent ethyl into their recommendations, Bhatt thinks the findings of REDUCE-IT are already actionable, especially since icosapent ethyl has shown to be “highly cost-effective.

“I wouldn’t wait for all that good science before implementing the results of REDUCE-IT,” Bhatt said. – by Phil Neuffer

Reference:

Bhatt DL. Treatment of High-Risk Patients with CVD and Elevated Triglycerides: REDUCE IT and Beyond. Presented at: Cardiometabolic Health Congress; Oct. 10-13, 2019; Chicago.

Disclosures: The REDUCE-IT trail was funded by Amarin Pharmaceuticals. Bhatt reports he has financial ties with numerous drug and device companies, including receiving research funding from Amarin.

CHICAGO — Findings of cardiovascular benefit with icosapent ethyl treatment from the REDUCE-IT trial have already revealed actionable clinical implications, but determining whether triglyceride reductions or eicosapentaenoic acid increases are the key mechanisms will be the focus of continuing research, according to a speaker at the Cardiometabolic Heath Congress.

Deepak L. Bhatt

“Regarding triglycerides, there is not really too much question anymore that these are indeed a causal risk factor; not just a risk marker but on the pathway to atherosclerosis,” Cardiology Today Editorial Board Member Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, said during a presentation, adding that “there are a number of promising therapies for hypertriglyceridemia,” highlighting the targeting of RNA as “particularly promising.”

In contrast, Bhatt said that low-dose omega-3 mixtures don’t appear to make much of a difference based on the available data, but that hasn’t stopped the use of fish oil supplements.

“I think there’s a lot of use of supplements out there and I would discourage the use of these agents that are ineffective and expensive,” Bhatt said.

REDUCE-IT primary findings

Although the effects of these fatty acids in lower doses are negligible, icosapent ethyl (Vascepa, Amarin Pharmaceuticals) is a “transformational medicine” that, much like penicillin and paclitaxel, is created with naturally occurring elements, according to Bhatt. It was tested for its cardiovascular benefits in the REDUCE-IT trial.

As part of the trial, researchers randomly assigned adults aged at least 45 years with cardiovascular disease and triglycerides of at least 150 mg/dL to either a daily 4 g dose of icosapent ethyl (n = 4,089; mean age, 54 years; 28% women) or placebo (n = 4,090; mean age, 64 years, 29% women). Participants were then followed for roughly 5 years, according to Bhatt, with the researchers evaluating how long it took for participants to experience a major CV event, including CV death, myocardial infarction, stroke, coronary revascularization or unstable angina.

After 5 years, the researchers found that those taking icosapent ethyl were at a lower risk for this primary endpoint compared with those taking placebo (HR = 0.75; 95% CI, 0.68-0.83). In addition, those taking icosapent ethyl were at lower risk for CV death, MI or stroke than those taking placebo (HR = 0.74; 95% CI, 0.65-0.83) and were also at lower risk for multiple events, with total event risk reduced by 30% for those taking icosapent ethyl compared with those taking placebo (RR = 0.7; 95% CI, 0.62-0.78).

PAGE BREAK

Bhatt also noted that most adverse event rates were “virtually identical,” although there was an “imbalance” in serious bleeding events and higher rates of atrial fibrillation for those taking icosapent ethyl compared with those taking placebo.

The foundation for the REDUCE-IT trial is a strong one. Prior to REDUCE-IT, the JELIS and CHERRY trials were a “great one-two punch” in that they revealed that eicosapentaenoic acid may have CV benefits, although Bhatt noted that both studies had limitations in study design. In addition, the MARINE and ANCHOR trials provided more specific building blocks for the REDUCE-IT trial as they examined the safety and efficacy of icosapent ethyl specifically.

Completing the story

While many of the findings of REDUCE-IT are important, Bhatt also highlighted other portions of the data that are worth considering and may provide mechanistic evidence. For example, Bhatt noted that trial data revealed a larger change in numerous biomarkers compared with baseline for those taking icosapent ethyl compared with those taking placebo. In particular, those taking icosapent ethyl had a 19.7% greater reduction in triglycerides (P < .0001) and a 358.8% greater increase in eicosapentaenoic acid (P < .0001) compared with those taking placebo.

“My own feeling is that what really drove the benefit in this trial ... was this large change in levels of [eicosapentaenoic acid],” Bhatt said.

In addition to the benefits shown, the REDUCE-IT trial has also produced more robust results in comparison with other trials aimed at evaluating the reduction of triglycerides, including the JELIS, GISSI-P, HPS2-THRIVE, AIM-HIGH, ACCORD-Lipid and FIELD trials.

A unique aspect of the REDUCE-IT trial was the incorporation of triglyceride variability. Bhatt explained that an average of triglyceride measures taken during screening and those taken after the researchers randomly assigned participants to a regimen was used to set baseline triglycerides. The researchers also created triglyceride tertiles and found “consistent benefits” with icosapent ethyl treatment, although the HR was lowest for those with a baseline triglyceride level of more than 250 mg/dL (HR = 0.68; 95% CI, 0.57-0.8).

“In relative terms, consistent similar benefits statistically across tertiles but in absolute terms, maybe a little bit more bang for your buck as the tertiles go up,” Bhatt said, while adding that when looking at “achieved triglycerides,” there was also consistency in the results.

“Some have said this is evidence that there is a triglyceride-independent benefit of icosapent ethyl, and I happen to agree,” Bhatt said. “I do think triglycerides are part of the story but not the whole story.”

PAGE BREAK

The rest of that story may be found in how eicosapentaenoic acids provide benefits for endothelial dysfunction and oxidative stress, inflammation and plaque growth and unstable plaque as well as in blood pressure reduction, according to Bhatt, who also noted that how eicosapentaenoic acids interact with cellular membranes may play a role. These and other factors will be evaluated in studies currently being conducted, including EVAPORATE, STRENGTH and PROMINENT. Bhatt said the latter two having the potential to shed even more light on REDUCE-IT’s findings.

“There are other trials that will come that will help really determine whether it’s an [eicosapentaenoic acid] story or a triglyceride-lowering story,” Bhatt said. “When these two trials are done, we’ll see is it any omega-3 at a high dose in STRENGTH or is it any triglyceride lowering in PROMINENT that leads to cardiovascular benefit. I think at the end of both these series of trials we’ll know if it’s just an [eicosapentaenoic acid] at 4 g per day story as in REDUCE-IT, or whether it can be generalized.”

With professional organizations such as the American Diabetes Association, American Heart Association and European Medicines Agency incorporating some of the research about icosapent ethyl into their recommendations, Bhatt thinks the findings of REDUCE-IT are already actionable, especially since icosapent ethyl has shown to be “highly cost-effective.

“I wouldn’t wait for all that good science before implementing the results of REDUCE-IT,” Bhatt said. – by Phil Neuffer

Reference:

Bhatt DL. Treatment of High-Risk Patients with CVD and Elevated Triglycerides: REDUCE IT and Beyond. Presented at: Cardiometabolic Health Congress; Oct. 10-13, 2019; Chicago.

Disclosures: The REDUCE-IT trail was funded by Amarin Pharmaceuticals. Bhatt reports he has financial ties with numerous drug and device companies, including receiving research funding from Amarin.

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