The current study is of a major clinical significance as it shows that EPA lowers ischemic cardiovascular events by 25% in high rick CVD patients who are already receiving statin therapy. The EPA treated patients, however, experienced more hospitalizations for atrial fibrillation and a higher propensity for serious bleeding than placebo. Findings are remarkable as they come from a major randomized clinical trial (REDUCE IT). About 8,000 patients were followed for 5 years.
This outcome data is in accordance with established observation and notion that hypertriglyceridemia is an independent risk factor for cardiovascular disease, mainly via increased inflammation and concentration of the non-HDL cholesterol. Prior clinical studies have also shown that EPA lowers non-HDL cholesterol more than DHA.
Omega-3s, EPA and DHA, are two key ingredients of fish oil. A stable and pure form of EPA has been FDA approved for very high serum triglycerides >500 mg/dL since 2012. It is marketed under the brand-name vascepa. Lovaza, a mixture of EPA and DHA, has also been approved by FDA since 2004 for severe hypertriglyceridemia.
I anticipate that in the future NLA, ACC/AHA, AACE and ADA guidelines will reflect and incorporate the current findings of REDUCE IT.
GT
Also see:
N E J M
REDUCE IT
January 2019
BACKGROUND
Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl (IE), a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events.
METHODS
We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135-500 mg/dL mg/dL and a LDLc level of 40-100 mg/dL. The patients were randomly assigned to receive 2 g of IE twice daily (total daily dose, 4 g) or placebo.
- The observed cardiovascular benefits were similar across baseline levels of triglycerides (<150, 150-200, >200 mg/dL). In addition, the significantly lower risk of major adverse cardiovascular events with IE than with placebo appeared to occur irrespective of the attained triglyceride level at 1 year (≥150 or <150 mg/dL), which suggests that the cardiovascular risk reduction was not associated with attainment of a more normal triglyceride level.
- These observations suggest that at least some of the effect of IE that resulted in a lower risk of ischemic events than that with placebo may be explained by metabolic effects other than a reduction of triglyceride levels.
Mechanisms responsible for the benefit of IE observed in REDUCE-IT are currently not known. The timing of the divergence of the Kaplan–Meier event curves suggests a delayed onset of benefit, which may reflect the time that is needed for a benefit from a reduction in triglyceride levels to be realized or may indicate that other mechanisms are involved. The modestly higher rate of bleeding events with IE suggests that there may be an antithrombotic mechanism of action. However, it is unlikely that an antithrombotic effect would reduce the rate of elective revascularization. Also, if the full explanation involved an antiplatelet or anticoagulant effect, one might expect a large increase in the rate of major bleeding events, which was not observed. It is possible that membrane-stabilizing effects could explain part of the benefit.
Stabilization or regression of coronary plaque (or both) may also play a part. Our observation of lower rates of cardiac arrest and sudden cardiac death with IE than with placebo in the current trial might support that mechanism, although these findings should be viewed as exploratory. It is also possible that the difference in hsCRP level observed in REDUCE-IT may contribute to the benefit; the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) showed a significant reduction in the risk of ischemic events with treatment targeted at inflammation. Blood samples obtained during REDUCE-IT have been banked for biomarker and genetic analyses that may provide more information regarding mechanisms of action.
Ongoing trials of moderate-to-high doses of pure EPA ethyl ester will provide further information on the effects of these agents. These trials include the Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and EPA, a secondary prevention outcomes trial involving statin-treated patients in Japan, and the Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy, which is examining changes in coronary plaque over 9-18 months.
Our trial has certain limitations. First, at the time the trial was designed, there was relatively little use of ezetimibe or data supporting its use. However, subgroup analyses do not suggest a differential benefit for patients taking ezetimibe. Similarly, PCSK9 inhibitors were not available for the majority of the patients in the trial. Second, if mineral oil in the placebo affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL cholesterol levels between the groups would not be likely to explain the 25% lower risk observed with IE, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDLc among the patients in the placebo group. Although JELIS was designed as an open-label study that did not use a mineral oil placebo, it showed a 19% lower risk of ischemic events with statin therapy plus EPA than with statin therapy alone.
In conclusion, among patients with elevated triglyceride levels who were receiving statin therapy, the risk of major ischemic events, including cardiovascular death, was significantly lower with 2 g of IE BID (total daily dose, 4 g) than with placebo.
- A primary end-point event occurred in 17.2% of the patients in the IE group, as compared with 22.0% of the patients in the placebo group (HR 0.75, p<0.001)
- The key secondary end point was 11.2% and 14.8% (HR 0.74, p<0.001).
- The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the IE group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; HR 0.80, p=0.03).
- A larger percentage of patients in the IE group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, p=0.004).
- Serious bleeding events occurred in 2.7% of the patients in the IE group and in 2.1% in the placebo group (P=0.06).
CONCLUSIONS
Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of IE twice daily than among those who received placebo.
More from the publication:
Among patients with cardiovascular risk factors who are receiving treatment for secondary or primary prevention, the rates of cardiovascular events remain high. Even in patients receiving appropriate treatment with statins, a substantial residual cardiovascular risk remains. In such patients, an elevated triglyceride level serves as an independent marker for an increased risk of ischemic events, as shown in epidemiologic and mendelian randomization studies.
In randomized trials, medications that reduce triglyceride levels, such as extended-release niacin and fibrates, have not reduced the rates of cardiovascular events when administered in addition to appropriate medical therapy, including statins. Contemporary trials and recent meta-analyses of n−3 fatty acid products have not shown a benefit in patients receiving statin therapy.
In the Japan EPA Lipid Intervention Study (JELIS), 18,645 Japanese patients with hypercholesterolemia were randomly assigned to receive either low-intensity statin therapy plus 1.8 g of eicosapentaenoic acid (EPA) daily or statin therapy alone (there was no placebo group). The risk of major coronary events was significantly lower, by 19%, in the group that received EPA plus statin therapy than in the group that received statin therapy alone.
These considerations led to the design of the Reduction of Cardiovascular Events with IE–Intervention Trial (REDUCE-IT). IE is a highly purified and stable EPA ethyl ester that has been shown to lower triglyceride levels and is used as an adjunct to diet in adult patients who have triglyceride levels >500 mg/dL. In addition, IE may have anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties. We hypothesized that the risk of cardiovascular events would be lower with IE therapy than with placebo among patients in whom elevated triglyceride levels served as a marker of residual risk despite statin therapy.
In REDUCE-IT, the risk of the PRIMARY composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, assessed in a time-to-event analysis, was significantly lower, by 25%, among the patients who received 2 g of IE BID than among those who received placebo, corresponding to an absolute between-group difference of 4.8 percentage points in the rate of the end point and a number needed to treat of 21.
The risk of the key SECONDARY composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis was also significantly lower, by 26%, in the IE group than in the placebo group, corresponding to an absolute between-group difference of 3.6 percentage points in the rate of the end point and a number needed to treat of 28.
Prespecified hierarchical testing of other secondary end points revealed that the risks of a variety of fatal and nonfatal ischemic events were lower in the IE group than in the placebo group, including a 20% lower risk of cardiovascular death. The benefits were observed against a background of appropriate statin use among patients who had a median LDLc >75.0 mg/dL at baseline.
The overall rates of adverse events were similar in the trial groups. Serious adverse events related to BLEEDING occurred in more patients in the IE group than in the placebo group, although the overall rates were low; there were no fatal bleeding events in either group, and the rates of adjudicated hemorrhagic stroke, serious central nervous system bleeding, and serious gastrointestinal bleeding were not significantly higher in the IE group than in the placebo group.
The rate of hospitalization for atrial fibrillation or flutter was significantly higher in the IE group than in the placebo group, although the rates were low. The rates of adverse events and serious adverse events leading to discontinuation of trial drug were similar in the two groups.
The results of REDUCE-IT stand apart from the negative findings of several contemporary trials of other agents that also lower triglyceride levels, including other n−3 fatty acids, extended-release niacin, fenofibrate, and cholesteryl ester transfer protein inhibitors. It is not known whether the lack of benefit from n−3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to DHA. Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials of n−3 fatty acids.
JELIS, which compared a combination of statin therapy and pure EPA with statin therapy alone, showed that the risk of ischemic events was significantly lower in the group that received the combination treatment than in the group that received statin therapy alone. Although the dose of EPA administered in JELIS (1.8 g daily) was lower than the EPA-equivalent dose used in REDUCE-IT (4 g daily), it resulted in a plasma EPA level (170 μg/mL in a Japanese population) similar to that attained in a previous 12-week lipid study in which a total daily dose of 4 g of IE was used in a Western population (183 μg/mL) and similar to that attained in the current trial.
However, unlike the current trial, JELIS included an open-label design without a placebo group, used a low-intensity statin, and was conducted in a single country; patients also had higher levels of LDL cholesterol at baseline (182 mg/dL [4.71 mmol per liter] before initiation of statin therapy) and lower baseline triglyceride values (151 mg/dL) than the patients in REDUCE-IT.
Metabolic data provide evidence that IE–based formulations do not raise LDLc levels, whereas DHA-based formulations do. The results of the current trial should not be generalized to other n−3 fatty acid preparations — in particular, dietary-supplement preparations of n−3 fatty acid mixtures, which are variable and unregulated, and which have not been shown to have clinical benefit.
A triglyceride level of ≥150 mg/dL was an initial inclusion criterion in REDUCE-IT (although the required level was subsequently changed to ≥200 mg/dL); however, owing to allowance for variability in these levels, 10.3% of enrolled patients had triglyceride levels <150 mg/dL at baseline.
- The observed cardiovascular benefits were similar across baseline levels of triglycerides (<150, 150-200, >200 mg/dL). In addition, the significantly lower risk of major adverse cardiovascular events with IE than with placebo appeared to occur irrespective of the attained triglyceride level at 1 year (≥150 or <150 mg/dL), which suggests that the cardiovascular risk reduction was not associated with attainment of a more normal triglyceride level.
- These observations suggest that at least some of the effect of IE that resulted in a lower risk of ischemic events than that with placebo may be explained by metabolic effects other than a reduction of triglyceride levels.
Mechanisms responsible for the benefit of IE observed in REDUCE-IT are currently not known. The timing of the divergence of the Kaplan–Meier event curves suggests a delayed onset of benefit, which may reflect the time that is needed for a benefit from a reduction in triglyceride levels to be realized or may indicate that other mechanisms are involved. The modestly higher rate of bleeding events with IE suggests that there may be an antithrombotic mechanism of action. However, it is unlikely that an antithrombotic effect would reduce the rate of elective revascularization. Also, if the full explanation involved an antiplatelet or anticoagulant effect, one might expect a large increase in the rate of major bleeding events, which was not observed. It is possible that membrane-stabilizing effects could explain part of the benefit.
Stabilization or regression of coronary plaque (or both) may also play a part. Our observation of lower rates of cardiac arrest and sudden cardiac death with IE than with placebo in the current trial might support that mechanism, although these findings should be viewed as exploratory. It is also possible that the difference in hsCRP level observed in REDUCE-IT may contribute to the benefit; the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) showed a significant reduction in the risk of ischemic events with treatment targeted at inflammation. Blood samples obtained during REDUCE-IT have been banked for biomarker and genetic analyses that may provide more information regarding mechanisms of action.
Ongoing trials of moderate-to-high doses of pure EPA ethyl ester will provide further information on the effects of these agents. These trials include the Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and EPA, a secondary prevention outcomes trial involving statin-treated patients in Japan, and the Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy, which is examining changes in coronary plaque over 9-18 months.
Our trial has certain limitations. First, at the time the trial was designed, there was relatively little use of ezetimibe or data supporting its use. However, subgroup analyses do not suggest a differential benefit for patients taking ezetimibe. Similarly, PCSK9 inhibitors were not available for the majority of the patients in the trial. Second, if mineral oil in the placebo affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL cholesterol levels between the groups would not be likely to explain the 25% lower risk observed with IE, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDLc among the patients in the placebo group. Although JELIS was designed as an open-label study that did not use a mineral oil placebo, it showed a 19% lower risk of ischemic events with statin therapy plus EPA than with statin therapy alone.
In conclusion, among patients with elevated triglyceride levels who were receiving statin therapy, the risk of major ischemic events, including cardiovascular death, was significantly lower with 2 g of IE BID (total daily dose, 4 g) than with placebo.
- The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.
- The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke [without coronary revascularization, or unstable angina].
RESULTS
A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years.
- A primary end-point event occurred in 17.2% of the patients in the IE group, as compared with 22.0% of the patients in the placebo group (HR 0.75, p<0.001)
- The key secondary end point was 11.2% and 14.8% (HR 0.74, p<0.001).
- The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the IE group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; HR 0.80, p=0.03).
- A larger percentage of patients in the IE group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, p=0.004).
- Serious bleeding events occurred in 2.7% of the patients in the IE group and in 2.1% in the placebo group (P=0.06).
CONCLUSIONS
Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of IE twice daily than among those who received placebo.
More from the publication:
Among patients with cardiovascular risk factors who are receiving treatment for secondary or primary prevention, the rates of cardiovascular events remain high. Even in patients receiving appropriate treatment with statins, a substantial residual cardiovascular risk remains. In such patients, an elevated triglyceride level serves as an independent marker for an increased risk of ischemic events, as shown in epidemiologic and mendelian randomization studies.
In randomized trials, medications that reduce triglyceride levels, such as extended-release niacin and fibrates, have not reduced the rates of cardiovascular events when administered in addition to appropriate medical therapy, including statins. Contemporary trials and recent meta-analyses of n−3 fatty acid products have not shown a benefit in patients receiving statin therapy.
In the Japan EPA Lipid Intervention Study (JELIS), 18,645 Japanese patients with hypercholesterolemia were randomly assigned to receive either low-intensity statin therapy plus 1.8 g of eicosapentaenoic acid (EPA) daily or statin therapy alone (there was no placebo group). The risk of major coronary events was significantly lower, by 19%, in the group that received EPA plus statin therapy than in the group that received statin therapy alone.
These considerations led to the design of the Reduction of Cardiovascular Events with IE–Intervention Trial (REDUCE-IT). IE is a highly purified and stable EPA ethyl ester that has been shown to lower triglyceride levels and is used as an adjunct to diet in adult patients who have triglyceride levels >500 mg/dL. In addition, IE may have anti-inflammatory, antioxidative, plaque-stabilizing, and membrane-stabilizing properties. We hypothesized that the risk of cardiovascular events would be lower with IE therapy than with placebo among patients in whom elevated triglyceride levels served as a marker of residual risk despite statin therapy.
In REDUCE-IT, the risk of the PRIMARY composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina, assessed in a time-to-event analysis, was significantly lower, by 25%, among the patients who received 2 g of IE BID than among those who received placebo, corresponding to an absolute between-group difference of 4.8 percentage points in the rate of the end point and a number needed to treat of 21.
The risk of the key SECONDARY composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in a time-to-event analysis was also significantly lower, by 26%, in the IE group than in the placebo group, corresponding to an absolute between-group difference of 3.6 percentage points in the rate of the end point and a number needed to treat of 28.
Prespecified hierarchical testing of other secondary end points revealed that the risks of a variety of fatal and nonfatal ischemic events were lower in the IE group than in the placebo group, including a 20% lower risk of cardiovascular death. The benefits were observed against a background of appropriate statin use among patients who had a median LDLc >75.0 mg/dL at baseline.
The overall rates of adverse events were similar in the trial groups. Serious adverse events related to BLEEDING occurred in more patients in the IE group than in the placebo group, although the overall rates were low; there were no fatal bleeding events in either group, and the rates of adjudicated hemorrhagic stroke, serious central nervous system bleeding, and serious gastrointestinal bleeding were not significantly higher in the IE group than in the placebo group.
The rate of hospitalization for atrial fibrillation or flutter was significantly higher in the IE group than in the placebo group, although the rates were low. The rates of adverse events and serious adverse events leading to discontinuation of trial drug were similar in the two groups.
The results of REDUCE-IT stand apart from the negative findings of several contemporary trials of other agents that also lower triglyceride levels, including other n−3 fatty acids, extended-release niacin, fenofibrate, and cholesteryl ester transfer protein inhibitors. It is not known whether the lack of benefit from n−3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to DHA. Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials of n−3 fatty acids.
JELIS, which compared a combination of statin therapy and pure EPA with statin therapy alone, showed that the risk of ischemic events was significantly lower in the group that received the combination treatment than in the group that received statin therapy alone. Although the dose of EPA administered in JELIS (1.8 g daily) was lower than the EPA-equivalent dose used in REDUCE-IT (4 g daily), it resulted in a plasma EPA level (170 μg/mL in a Japanese population) similar to that attained in a previous 12-week lipid study in which a total daily dose of 4 g of IE was used in a Western population (183 μg/mL) and similar to that attained in the current trial.
However, unlike the current trial, JELIS included an open-label design without a placebo group, used a low-intensity statin, and was conducted in a single country; patients also had higher levels of LDL cholesterol at baseline (182 mg/dL [4.71 mmol per liter] before initiation of statin therapy) and lower baseline triglyceride values (151 mg/dL) than the patients in REDUCE-IT.
Metabolic data provide evidence that IE–based formulations do not raise LDLc levels, whereas DHA-based formulations do. The results of the current trial should not be generalized to other n−3 fatty acid preparations — in particular, dietary-supplement preparations of n−3 fatty acid mixtures, which are variable and unregulated, and which have not been shown to have clinical benefit.
A triglyceride level of ≥150 mg/dL was an initial inclusion criterion in REDUCE-IT (although the required level was subsequently changed to ≥200 mg/dL); however, owing to allowance for variability in these levels, 10.3% of enrolled patients had triglyceride levels <150 mg/dL at baseline.
- The observed cardiovascular benefits were similar across baseline levels of triglycerides (<150, 150-200, >200 mg/dL). In addition, the significantly lower risk of major adverse cardiovascular events with IE than with placebo appeared to occur irrespective of the attained triglyceride level at 1 year (≥150 or <150 mg/dL), which suggests that the cardiovascular risk reduction was not associated with attainment of a more normal triglyceride level.
- These observations suggest that at least some of the effect of IE that resulted in a lower risk of ischemic events than that with placebo may be explained by metabolic effects other than a reduction of triglyceride levels.
Mechanisms responsible for the benefit of IE observed in REDUCE-IT are currently not known. The timing of the divergence of the Kaplan–Meier event curves suggests a delayed onset of benefit, which may reflect the time that is needed for a benefit from a reduction in triglyceride levels to be realized or may indicate that other mechanisms are involved. The modestly higher rate of bleeding events with IE suggests that there may be an antithrombotic mechanism of action. However, it is unlikely that an antithrombotic effect would reduce the rate of elective revascularization. Also, if the full explanation involved an antiplatelet or anticoagulant effect, one might expect a large increase in the rate of major bleeding events, which was not observed. It is possible that membrane-stabilizing effects could explain part of the benefit.
Stabilization or regression of coronary plaque (or both) may also play a part. Our observation of lower rates of cardiac arrest and sudden cardiac death with IE than with placebo in the current trial might support that mechanism, although these findings should be viewed as exploratory. It is also possible that the difference in hsCRP level observed in REDUCE-IT may contribute to the benefit; the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) showed a significant reduction in the risk of ischemic events with treatment targeted at inflammation. Blood samples obtained during REDUCE-IT have been banked for biomarker and genetic analyses that may provide more information regarding mechanisms of action.
Ongoing trials of moderate-to-high doses of pure EPA ethyl ester will provide further information on the effects of these agents. These trials include the Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and EPA, a secondary prevention outcomes trial involving statin-treated patients in Japan, and the Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy, which is examining changes in coronary plaque over 9-18 months.
Our trial has certain limitations. First, at the time the trial was designed, there was relatively little use of ezetimibe or data supporting its use. However, subgroup analyses do not suggest a differential benefit for patients taking ezetimibe. Similarly, PCSK9 inhibitors were not available for the majority of the patients in the trial. Second, if mineral oil in the placebo affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL cholesterol levels between the groups would not be likely to explain the 25% lower risk observed with IE, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDLc among the patients in the placebo group. Although JELIS was designed as an open-label study that did not use a mineral oil placebo, it showed a 19% lower risk of ischemic events with statin therapy plus EPA than with statin therapy alone.
In conclusion, among patients with elevated triglyceride levels who were receiving statin therapy, the risk of major ischemic events, including cardiovascular death, was significantly lower with 2 g of IE BID (total daily dose, 4 g) than with placebo.