处方EPA衍生物对心脏的有益作用可提高血清EPA水平 Boosts in serum EPA levels from prescription fish oil drive heart benefits

News Release 30-Mar-2020

Editor’s note: Icosapent ethyl is not a component from fish oil. Rather, it is made from a fish borne omega 3 fatty acid called eicosapentaenoic acid (EPA). So it is a synthetic drug.

As with lowering LDL, raising EPA with icosapent ethyl helped lower CVD risk, study finds

American College of Cardiology

Higher levels of the omega-3 fatty acid eicosapentaenoic acid (EPA) found in the blood–and not a decrease in triglyceride levels as originally thought–appear to explain the striking reductions in cardiovascular events and deaths seen among people taking 4 grams daily of the prescription fish oil, icosapent ethyl, according to findings from a REDUCE-IT substudy presented at the American College of Cardiology’s Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

“A major missing piece of the puzzle, and what many clinicians want to know, is how icosapent ethyl actually works to produce such dramatic cardiovascular risk lowering,” said Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and lead author of the current study. “On-treatment EPA levels achieved via the drug strongly correlated with lower rates of cardiovascular events, heart attack, stroke, coronary revascularization procedures, unstable angina, sudden cardiac arrest, new heart failure, or death for any reason.”

REDUCE-IT enrolled 8,179 patients at 473 sites in 11 countries who had elevated cardiovascular risk and were already being treated with statins. The trial found that taking a high dose of icosapent ethyl cut the combined rate of first and subsequent nonfatal heart attacks, strokes, cardiovascular deaths, procedures for coronary artery disease such as stenting, or hospitalizations for unstable angina by 25% and 30%, respectively, over a median of 4.9 years of follow-up. Most patients in the trial were already on antiplatelet therapy, ACE-inhibitors/ARBs, beta blockers, aspirin and statins, which, researchers said, provided reassurance that icosapent ethyl, by itself, offered separate and incremental benefit.

Prior to REDUCE-IT, icosapent ethyl was approved by the U.S. Food and Drug Administration (FDA) for people with triglycerides above 500 mg/dL, so Bhatt said many people understandably thought the study drug reduced cardiovascular events primarily by lowering triglycerides. However, Bhatt said the current study, which looked at the association between blood serum levels of EPA achieved on icosapent ethyl and cardiovascular outcomes, found the lion’s share of the drug’s remarkably large cardiovascular benefit is driven by achieved EPA levels.

“Changes in triglycerides levels and other cardiovascular risk markers, including LDL, HDL, apoB and CRP, appear to be responsible for a significantly lesser portion of the overall observed benefit,” he said. “I think this finding is going to usher in a whole new era of cardiovascular therapies. We are, in a sense, where we were with statins when the first one came out.”

As part of the analysis, Bhatt and his team first looked at EPA levels prior to randomization to determine whether the drug worked differently based on a person’s initial baseline EPA level, which may reflect a diet high in fish consumption or genetics. But they found that regardless of patients’ initial serum EPA levels, they derived a similar and large degree of cardiovascular benefit. Data on baseline EPA were missing for 14% patients, but the baseline characteristics and outcomes were similar between patients with and without missing data.

The researchers then examined achieved EPA levels on the drug compared with placebo, grouping patients into thirds, or tertiles, ranging from the lowest to highest levels of EPA and averaged across visits. Achieved EPA within the icosapent ethyl group was strongly associated with cardiovascular events, and each of the tertiles showed a significant relative risk reduction in cardiovascular events.

They examined on-treatment EPA levels from lowest to highest and found significant associations with all measured cardiovascular outcomes. “The higher the EPA level in their blood, the lower the rates of the different cardiovascular events, cardiovascular deaths and even total mortality,” Bhatt said.

Overall, the drug significantly increased serum EPA levels by 386% from baseline to one-year compared with placebo. Levels of docosahexaenoic acid (DHA), which is another omega-3 fatty acid also found in oily fish like salmon, decreased by 2.9%, which Bhatt said suggests the cardiovascular benefits are clearly from EPA and not DHA.

Researchers also examined the relationship between on-treatment EPA levels and several other cardiovascular outcomes, though analyses for bleeding and atrial fibrillation were not yet available. While there were no significant reductions in heart failure in REDUCE-IT, among patients with the highest on-treatment EPA levels, there was a significant reduction in hospitalizations for new heart failure with the drug versus placebo, which Bhatt said is quite remarkable. There were also significant associations between on-treatment EPA levels and lower risks of sudden cardiac death and cardiac arrest, further validating what was seen in the overall trial.

Experts don’t know why some people are able to achieve higher serum EPA levels and others are not. Bhatt and his team accounted for whether patients took the drug, but there may be other influencing factors, such as how someone metabolizes EPA, their body size or their genetics–this needs further study.

Bhatt said the EPA levels attained on the drug are well beyond what can be achieved with diet or dietary supplements. He said that the study drug is a unique prescription medicine and that the results do not apply to other omega-3 products or to dietary supplement formulations, which are not approved or strictly regulated by the FDA and which, per the FDA, have not demonstrated reliable or consistent cardiovascular risk reduction.

Based on the data from REDUCE-IT, the FDA in December 2019 expanded the icosapent ethyl label to be used as an add-on to maximally tolerated statin therapy to help reduce the risk of heart attack, stroke, coronary revascularization and unstable angina requiring hospitalization in adult patients with triglyceride levels ?150 mg/dL and either established cardiovascular disease or diabetes mellitus plus two or more additional risk factors for cardiovascular disease. Based on this, Bhatt said icosapent ethyl stands to benefit over 12 million patients in the U.S. alone.


REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for the work Bhatt did as the trial chair and as the international principal investigator.

ACC.20/WCC will take place March 28-30, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC20/#WCCardio for the latest news from the meeting.

The American College of Cardiology envisions a world where innovation and knowledge optimize cardiovascular care and outcomes. As the professional home for the entire cardiovascular care team, the mission of the College and its 54,000 members is to transform cardiovascular care and to improve heart health. The ACC bestows credentials upon cardiovascular professionals who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. The College also provides professional medical education, disseminates cardiovascular research through its world-renowned JACC Journals, operates national registries to measure and improve care and offers cardiovascular accreditation to hospitals and institutions. For more, visit acc.org.


血液中发现的Omega-3脂肪酸二十碳五烯酸(EPA)含量较高,而甘油三酯水平并未如最初所想的那样降低,这似乎可以解释每天服用4克维生素C的人心血管事件和死亡的显着减少。处方鱼油,二十碳五烯酸乙酯,根据REDUCE-IT子研究的结果,该研究在美国心脏病学会年度科学会议上与世界心脏病学会一起提交(ACC.20 / WCC)。

百翰姆介入性心血管项目执行董事Deepak L. Bhatt博士说:“难题的一个主要缺失之处,也是许多临床医生想知道的,是二十碳五烯酸乙酯如何真正发挥作用,从而大大降低了心血管疾病的风险。”和妇女医院,哈佛医学院的医学教授,也是本研究的主要作者。 “通过该药物获得的治疗中EPA水平与心血管事件,心脏病发作,中风,冠状动脉血运重建程序,不稳定的心绞痛,心脏骤停,新心脏衰竭或任何原因死亡的发生率降低密切相关。”

REDUCE-IT在11个国家/地区的473个地点招募了8179名患者,这些患者的心血管疾病风险较高,已经接受他汀类药物治疗。该试验发现,高剂量二十碳五碳乙酯可将首次和随后发生的非致命性心脏病,中风,心血管死亡,冠状动脉疾病(如置入支架)或不稳定型心绞痛的住院治疗的总发生率分别降低25%和30%。 ,平均随访时间为4.9年。研究人员说,该试验中的大多数患者已经在接受抗血小板治疗,ACEI / ARBs,β受体阻滞剂,阿司匹林和他汀类药物,这使研究人员确信,二十碳五烯酸乙酯本身可提供单独和递增的益处。

在REDUCE-IT之前,二十碳五烯酸乙酯已被美国食品药品监督管理局(FDA)批准用于甘油三酸酯含量超过500 mg / dL的人群,因此Bhatt说,许多人可以理解地认为,该研究药物主要通过降低甘油三酸酯来减少心血管事件。但是,巴特说,目前的研究调查了在二十碳五烯酸乙酯上获得的EPA血清水平与心血管结果之间的关系,发现该药物显着的巨大心血管益处中的最大份额是由达到的EPA水平驱动的。

他说:“甘油三酸酯水平和其他心血管危险标志物的变化,包括LDL,HDL,apoB和CRP,似乎在所观察到的总体收益中所占的比例要小得多。” “我认为这一发现将开启心血管疗法的一个全新时代。从某种意义上讲,我们是第一个问世时他汀类药物的治疗者。”

作为分析的一部分,Bhatt和他的团队在进行随机分组之前首先查看了EPA的水平,以确定药物是否基于人的初始基线EPA的水平而有所不同,这可能反映了鱼食或遗传学含量高的饮食。但是他们发现,不管患者最初的血清EPA水平如何,他们都能获得相似且很大程度的心血管益处。 14%的患者缺少有关基线EPA的数据,但是有和没有数据缺失的患者之间的基线特征和结果相似。


他们检查了从最低到最高的治疗中EPA水平,发现与所有测得的心血管结局均存在显着相关性。 Bhatt说:“他们血液中的EPA含量越高,不同心血管事件,心血管死亡甚至总死亡率的发生率就越低。”



专家不知道为什么有些人能够达到更高的血清EPA水平,而另一些人却没有。 Bhatt和他的团队解释了患者是否服用了这种药物,但可能还有其他影响因素,例如某人如何代谢EPA,其体型或遗传学,这需要进一步研究。


根据REDUCE-IT的数据,FDA在2019年12月扩大了icosapentethyl标签的使用范围,以最大程度耐受他汀类药物疗法,以帮助降低心脏病,中风,冠状动脉血运重建和不稳定心绞痛需要住院的风险在甘油三酸酯水平≥150mg / dL且已确定的心血管疾病或糖尿病加上两个或多个其他心血管疾病危险因素的成年患者中。基于这一点,巴特表示,仅在美国,二十碳五烯酸就能使超过1200万患者受益。

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