Meeting NewsPerspective

REDUCE-IT: Icosapent ethyl reduces ischemic events in high-risk patients

Deepak L. Bhatt
Deepak L. Bhatt

CHICAGO — In patients with elevated triglycerides at high CV risk despite statin therapy, icosapent ethyl was superior to placebo for reducing risk for ischemic events, according to results of the anticipated REDUCE-IT trial.

The trial of icosapent ethyl (Vascepa, Amarin Pharmaceuticals), a pharmaceutical-grade omega-3 fatty acid, enrolled 8,179 patients (median age, 64 years; 71% men) who had fasting triglycerides 135 mg/dL to 499 mg/dL despite taking statins and who had established CVD (70.7%) or diabetes plus other risk factors (29.3%). Patients were assigned icosapent ethyl 2 g twice daily or placebo and followed for a median of 4.9 years. All had LDL levels ranging from 41 mg/dL to 100 mg/dL.

Reduction in CV events

The primary endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina occurred less often in the icosapent ethyl group compared with the placebo group (17.2% vs. 22%; HR = 0.75; 95% CI, 0.68-0.83; P = .00000001; absolute difference, 4.8%; 95% CI, 3.1-6.5; number needed to treat to prevent one primary endpoint event = 21; 95% CI, 15-33), Cardiology Today’s Intervention Chief Medical Editor 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, reported at the American Heart Association Scientific Sessions.

Treatment with icosapent ethyl significantly reduced cardiovascular events, including a 20% reduction in cardiovascular death, a 31% reduction in heart attack, a 28% reduction in stroke and a low rate of adverse events,” Bhatt said during a presentation. “There was a consistent benefit across all subgroups, including in the primary and secondary prevention cohorts.”

The key secondary endpoint, defined as CV death, nonfatal MI or nonfatal stroke, was also lower in the icosapent ethyl group (11.2% vs. 14.8%; HR = 0.74; 95% CI, 0.65-0.83; P = .0000006; absolute difference, 3.6%; 95% CI, 2.1-5; number needed to treat to prevent one key secondary endpoint event = 28; 95% CI, 20-47).

The researchers also performed hierarchical testing of additional ischemic endpoints. In this analysis, the rates of the additional ischemic endpoints, including death from CV causes, were also lower in the icosapent ethyl group (4.3% vs. 5.2%; HR = 0.8; 95% CI, 0.66-0.98).

Carl E. Orringer
Carl E. Orringer

“The highly significant reductions in the primary and secondary cardiovascular endpoints in the presence of relatively modest effects of blood lipids and lipoproteins suggest the possibility that other properties of this drug such as the antithrombotic or anti-inflammatory effects” could have prompted the results, Carl E. Orringer, MD, FACC, FNLA, associate professor of medicine at University of Miami Miller School of Medicine, said during a discussant presentation at the press conference.

Hospitalization for atrial fibrillation or flutter occurred more often in the icosapent ethyl group (3.1% vs. 2.1%; P = .004) and there was a trend toward more serious bleeding events in the icosapent ethyl group (2.7% vs. 2.1%; P = .06), Bhatt and colleagues found.

All-cause death did not significantly differ between the groups (icosapent ethyl group, 6.7%; placebo group, 7.6%; HR = 0.87; 95% CI, 0.74-1.02; P = .09).

Median change in triglyceride levels between baseline and 1 year was –18.3% (–39 mg/dL) in the icosapent ethyl group and 2.2% (4.5 mg/dL) in the placebo group (difference, 19.7% or 44.5 mg/dL; P < .001).

During the study, LDL rose a median of 3.1% (2 mg/dL) in the icosapent ethyl group and 10.2% (7 mg/dL; difference, 6.6% or 5 mg/dL; P < .001) in the placebo group.

The treatment effect of icosapent ethyl on the primary endpoint was greater in patients who had baseline triglycerides of at least 200 mg/dL and baseline HDL of 35 mg/dL or less (P for interaction = .04), according to the accompanying manuscript simultaneously published in The New England Journal of Medicine.

Overall adverse events and adverse events leading to study drug discontinuation did not significantly differ between the groups.

Growing therapeutic armamentarium

Commenting on the findings, as the study population was 90% white, the agent should be studied more thoroughly in other races and ethnicities, Orringer said.

“Unlike other drugs shown to be effective as add-ons to statins, this one appears to work via a mechanism that is unrelated to LDL receptor expression,” Orringer said during the press conference. “We now have three therapies [icosapent ethyl, ezetimibe and PCSK9 inhibitors] proven in randomized controlled trials that show a favorable risk-benefit ratio for cardiovascular disease in combination with statin treatment. As this is the first study that showed this in hypertriglyceremic patients, we have a very important addition to our therapeutic armamentarium for these patients.” – by Erik Swain

References:

Bhatt DL, et al. LBS.01 – Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Bhatt DL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812792.

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

 

Deepak L. Bhatt
Deepak L. Bhatt

CHICAGO — In patients with elevated triglycerides at high CV risk despite statin therapy, icosapent ethyl was superior to placebo for reducing risk for ischemic events, according to results of the anticipated REDUCE-IT trial.

The trial of icosapent ethyl (Vascepa, Amarin Pharmaceuticals), a pharmaceutical-grade omega-3 fatty acid, enrolled 8,179 patients (median age, 64 years; 71% men) who had fasting triglycerides 135 mg/dL to 499 mg/dL despite taking statins and who had established CVD (70.7%) or diabetes plus other risk factors (29.3%). Patients were assigned icosapent ethyl 2 g twice daily or placebo and followed for a median of 4.9 years. All had LDL levels ranging from 41 mg/dL to 100 mg/dL.

Reduction in CV events

The primary endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina occurred less often in the icosapent ethyl group compared with the placebo group (17.2% vs. 22%; HR = 0.75; 95% CI, 0.68-0.83; P = .00000001; absolute difference, 4.8%; 95% CI, 3.1-6.5; number needed to treat to prevent one primary endpoint event = 21; 95% CI, 15-33), Cardiology Today’s Intervention Chief Medical Editor 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, reported at the American Heart Association Scientific Sessions.

Treatment with icosapent ethyl significantly reduced cardiovascular events, including a 20% reduction in cardiovascular death, a 31% reduction in heart attack, a 28% reduction in stroke and a low rate of adverse events,” Bhatt said during a presentation. “There was a consistent benefit across all subgroups, including in the primary and secondary prevention cohorts.”

The key secondary endpoint, defined as CV death, nonfatal MI or nonfatal stroke, was also lower in the icosapent ethyl group (11.2% vs. 14.8%; HR = 0.74; 95% CI, 0.65-0.83; P = .0000006; absolute difference, 3.6%; 95% CI, 2.1-5; number needed to treat to prevent one key secondary endpoint event = 28; 95% CI, 20-47).

The researchers also performed hierarchical testing of additional ischemic endpoints. In this analysis, the rates of the additional ischemic endpoints, including death from CV causes, were also lower in the icosapent ethyl group (4.3% vs. 5.2%; HR = 0.8; 95% CI, 0.66-0.98).

Carl E. Orringer
Carl E. Orringer

“The highly significant reductions in the primary and secondary cardiovascular endpoints in the presence of relatively modest effects of blood lipids and lipoproteins suggest the possibility that other properties of this drug such as the antithrombotic or anti-inflammatory effects” could have prompted the results, Carl E. Orringer, MD, FACC, FNLA, associate professor of medicine at University of Miami Miller School of Medicine, said during a discussant presentation at the press conference.

PAGE BREAK

Hospitalization for atrial fibrillation or flutter occurred more often in the icosapent ethyl group (3.1% vs. 2.1%; P = .004) and there was a trend toward more serious bleeding events in the icosapent ethyl group (2.7% vs. 2.1%; P = .06), Bhatt and colleagues found.

All-cause death did not significantly differ between the groups (icosapent ethyl group, 6.7%; placebo group, 7.6%; HR = 0.87; 95% CI, 0.74-1.02; P = .09).

Median change in triglyceride levels between baseline and 1 year was –18.3% (–39 mg/dL) in the icosapent ethyl group and 2.2% (4.5 mg/dL) in the placebo group (difference, 19.7% or 44.5 mg/dL; P < .001).

During the study, LDL rose a median of 3.1% (2 mg/dL) in the icosapent ethyl group and 10.2% (7 mg/dL; difference, 6.6% or 5 mg/dL; P < .001) in the placebo group.

The treatment effect of icosapent ethyl on the primary endpoint was greater in patients who had baseline triglycerides of at least 200 mg/dL and baseline HDL of 35 mg/dL or less (P for interaction = .04), according to the accompanying manuscript simultaneously published in The New England Journal of Medicine.

Overall adverse events and adverse events leading to study drug discontinuation did not significantly differ between the groups.

Growing therapeutic armamentarium

Commenting on the findings, as the study population was 90% white, the agent should be studied more thoroughly in other races and ethnicities, Orringer said.

“Unlike other drugs shown to be effective as add-ons to statins, this one appears to work via a mechanism that is unrelated to LDL receptor expression,” Orringer said during the press conference. “We now have three therapies [icosapent ethyl, ezetimibe and PCSK9 inhibitors] proven in randomized controlled trials that show a favorable risk-benefit ratio for cardiovascular disease in combination with statin treatment. As this is the first study that showed this in hypertriglyceremic patients, we have a very important addition to our therapeutic armamentarium for these patients.” – by Erik Swain

References:

Bhatt DL, et al. LBS.01 – Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Bhatt DL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812792.

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

 

    Perspective
    Donna K. Arnett

    Donna K. Arnett

    The REDUCE-IT trial showed that a very high dose of icosapent ethyl was highly effective in reducing triglycerides and in reducing the primary outcome. These patients had LDL well-controlled on a statin and the majority of them already had a CV event. They were all hypertriglyceridemic. This was a special population, and amongst it, this very high-dose eicosapentaenoic acid product was effective. What that says is this is a good therapeutic option if you have high triglyceride levels and other high-risk factors.

    We need to compare a combined fish oil product (eicosapentaenoic acid and docosahexaenoic acid) vs. the product from this study to see if we get equivalent results or whether the effect is limited to the eicosapentaenoic acid.

    • Donna K. Arnett, PhD, MSPH
    • Dean, College of Public Health
      Professor of Epidemiology
      University of Kentucky
      Past President, AHA

    Disclosures: Arnett reports no relevant financial disclosures.

    Perspective
    Kevin M. Pantalone

    Kevin M. Pantalone

    The REDUCE-IT CV outcome trial found icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, administered twice daily was associated with a 25% relative risk reduction on the composite endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization or unstable angina in patients with established CVD or diabetes with other risk factors, vs. placebo therapy (HR = 0.75; 95% CI, 0.68-0.83). Baseline LDL and triglyceride levels were 41 to 100 mg/dL and 135 to 499 mg/dL, respectively.  

    An elevated triglyceride level has long been considered to be a marker of residual CV risk despite statin therapy, but the effect of triglyceride lowering on CV risk in various patient populations has long been debated. REDUCE-IT provides strong support for the use of icosapent ethyl to lower CV risk in this patient population. After a median follow-up of 4.9 years, among patients with elevated triglyceride levels despite the use of statins, risk reduction was observed with icosapent ethyl therapy. The change in triglyceride levels during the duration of trial was modest (median reduction from baseline was 19.7% greater with icosapent ethyl vs. placebo [44.5 mg/dL]), whereas the median change in LDL cholesterol level increased slightly from baseline in both groups 3.1%, (2 mg/dL) in the icosapent ethyl group and 10.2% (7 mg/dL) in the placebo group. The greater rise in LDL observed in the placebo arm is thought to be related to mineral oil use reducing statin absorption. This theory would be supported by the rise in C-reactive protein observed in the placebo arm. This issue may have contributed to differences in outcomes between the groups. While it is hard to explain the magnitude of the observed risk reduction with icosapent ethyl being related to this issue in the placebo arm, it must be taken into consideration when drawing conclusions about the study.

    The results of this study do not necessarily mean lowering triglyceride levels in this population of patients reduces CV risk, rather, one can only conclude that the observed CV risk reduction is related to the icosapent ethyl therapy, perhaps, as the authors suggest, via anti-inflammatory, anti-oxidative, plaque-stabilizing and membrane-stabilizing properties.  Clinicians must avoid concluding that similar reductions in triglyceride levels afforded by other triglyceride-lowering therapies may also confer CV benefit. The icosapent ethyl therapy may be mitigating residual risk unrelated to triglyceride lowering.

    As clinicians, we need to ensure that the focus on CV risk reduction occurs across the spectrum of management. Clinicians from the various specialties need to collaborate and coordinate so that our high-risk CV patients readily receive type 2 diabetes and CV-related therapies that have been reported to reduce CV risk.

    • Kevin M. Pantalone, DO, ECNU, FACE
    • Staff Endocrinologist
      Director of Clinical Research
      Department of Endocrinology
      Cleveland Clinic

    Disclosures: Pantalone reports he has received consultant fees, speaking fees or research support from AstraZeneca, Eli Lilly, Merck, Novo Nordisk and Sanofi.

    Perspective

    I found REDUCE-IT very compelling. The trial was done very well. It is increasingly recognized that triglyceride-rich lipoproteins influence recurrent risk for CVD and future CV events.

    Does REDUCE-IT prove lowering triglycerides reduces CV risk? Probably not cleanly. Icosapent ethyl lowers triglycerides but seems to do several other things. It’s almost a polypill of sorts. It reduces triglyceride-rich lipoproteins, has an antithrombotic/antiplatelet effect, has a membrane-stabilizing effect and potentially has other effects as well. Regardless of the mechanism, the apparent relative reduction of 25% over 5 years is very similar to what has been observed in prior statin trials. Also, the association with reduced CVD mortality is compelling.

    A key concern is that the placebo is not an inert placebo. Individuals assigned mineral oil may have had absorption of other lipid-lowering medicines interfered with. There was a slightly higher LDL level among those individuals. I don’t think the difference in LDL explains the full apparent treatment effect. The difference in LDL was between 5 and 10 mg/dL. In statin trials, a difference of 40 mg/dL led to a similar relative risk reduction. So, one can’t say the results are fully explained by an increase in LDL from the placebo, but it probably affects our understanding of the true treatment effect, which is probably lower than 25%. This concern came up previously in the ANCHOR study of icosapent ethyl, which used the same placebo which had the same effect on LDL. This came up at the FDA hearing. When the REDUCE-IT results ultimately go to the FDA, this will be brought up again, though because the treatment effect was so large, I don’t think the FDA will attribute it all to the effects from the placebo.

    It’s not clear if stratifying patients by triglyceride levels is the best way to identify who is the best candidate for icosapent ethyl, given that it seems to have other effects. In the JELIS study, what correlated better with treatment effect was change in eicosapentaenoic acid level.

    While there are still many questions to be answered, the findings are compelling and provide a new tool in our armamentarium to treat patients with residual hypertriglyceridemia and atherosclerotic CVD.

    • Pradeep Natarajan, MD, MMSc
    • Director, Preventive Cardiology
      Corrigan Minehan Heart Center
      Massachusetts General Hospital
      Assistant Professor of Medicine
      Harvard Medical School

    Disclosures: Natarajan reports he received a grant from Amgen.

    See more from American Heart Association Scientific Sessions