Icosapent ethyl following acute coronary syndrome: the REDUCE-IT trial

Clinical trials, Icosapent ethyl, Acute coronary syndrome, Ischaemic events

Introduction

The REDUCE-IT [Reduction of Cardiovascular Events With Icosapent Ethyl (IPE)-Intervention Trial] trial showed robust reductions in ischaemic events with IPE vs. placebo, including reduced cardiovascular (CV) death, albeit with increased rates of bleeding, and of atrial fibrillation (AF).¹ These observations were confirmed in patients with prior myocardial infarction (MI).² Patients with recent (<12 months) acute coronary syndrome (ACS) are at very high risk of future CV events (including arrhythmias) for which they usually receive intensive antithrombotic therapy, which might increase bleeding risk with IPE. The benefit and safety of IPE in this specific patient subgroup are largely unknown and were explored in the present post hoc analysis of the original trial database.

Methods

REDUCE-IT was a double-blind, placebo-controlled trial that randomized 8179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides, and with either established CV disease or with diabetes and at least one additional risk factor, to either 4 g IPE or placebo.¹ The trial methods and results have previously been published.^1,3 The primary outcome was a composite of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary outcome was a composite of CV death, non-fatal MI, or non-fatal stroke.

Recent ACS (n = 840) was defined as MI or unstable angina within 12 months before randomization. In subsequent analyses, this group was compared with patients experiencing ACS ≥12 months before randomization (n = 3651). Time-to-first event was analysed by Kaplan–Meier analysis and compared using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a Cox proportional hazards model computed to determine the risk of primary and secondary outcomes according to the use of IPE vs. placebo in two-sided analyses. The model was stratified by the three randomization factors of CV risk category (established CV disease or diabetes plus risk factors), geographic region, and baseline ezetimibe use. Time-to-subsequent events was analysed using the Wei, Lin, and Weissfeld model to estimate HR and 95% CI for treatment effects. Total events were analysed by negative-binomial regression model to estimate rate ratio (RR) and 95% CI for treatment effects. Absolute risk reduction (ARR) was calculated as difference of event incidence rates between IPE and placebo. Statistical analyses were performed using SAS version 9.4 software (SAS Institute, Inc.).

Results

Among 8179 patients in REDUCE-IT, there were 840 (10.3%) with recent ACS <12 months before randomization. Median age was 59.5 years, 646 (76.9%) were male, 310 (36.9%) had diabetes, 839 (99.9%) were on statins, 805 (95.8%) received antiplatelet therapy, 584 (69.5%) received dual antiplatelet therapy (DAPT), 54 (6.4%) were on oral anticoagulant therapy, and 39 (4.6%) were on anticoagulant plus antiplatelet therapy. Median baseline triglyceride levels were 219.5 (interquartile range (IQR) 180.5–272.5) and 213.0 (IQR 174.0–274.0) mg/dL in the IPE and placebo groups, respectively (P = .36).

The median time elapsed between the index ACS and randomization was similar between IPE and placebo arms {5.5 (IQR 3.0–8.1) vs. 5.6 (IQR 3.2–8.4) months; P = .63}. Among recent ACS patients, use of anti-diabetic, anti-hypertensive, angiotensin-converting enzyme inhibitor, or beta-blocker therapies was similar between treatment arms, but DAPT use was lower in the IPE group compared with the placebo group (66.3% vs. 73.0%, P = .04), and rates of anticoagulant plus antiplatelet therapy were higher in the IPE group (6.2% vs. 2.9%, P = .02). Median study follow-up time was 4.75 years. Maximum follow-up time was 5.94 years.

Icosapent ethyl reduced the incidence of the first primary composite outcome by 37% (HR 0.63; 95% CI 0.48–0.84, P = .002) and total primary composite outcomes by 36% (RR 0.64; 95% CI 0.45–0.90, P = .01) (Figure 1). Absolute risk reduction in first primary outcome with IPE was 9.3%, (18.7% vs. 28.0%), number needed to treat (NNT) being 11 (95% CI 7–28). In contrast, these benefits tended to be less among the 3651 patients with ACS ≥12 months before randomization, in whom the relative risk reduction (RRR) was 22.0% and the ARR was 4.7% (NNT = 21) (HR 0.78; 95% CI 0.68–0.90, P = .0004) (interaction between recent and non-recent ACS P = .17). In recent ACS patients, IPE reduced the incidence of the first key secondary composite outcome by 36% (HR 0.64; 95% CI 0.44–0.92, P = .01) and total key secondary composite outcomes by 28% (RR 0.72; 95% CI 0.47–1.09, P = .12).

Figure 1

(A) First and subsequent events for the primary composite outcome in patients with recent ACS. (B) Cumulative incidence curves of the primary composite outcome in patients with recent ACS

In recent ACS patients, IPE lowered the composite of CV death and non-fatal MI 36% (HR 0.64; 95% CI 0.43–0.96, P = .03) with an ARR of 5.0%, and lowered urgent or emergent revascularization 44% (HR 0.56; 95% CI 0.36–0.87, P = .009) with an ARR of 5.1%.

In contrast, among recent ACS patients, the proportion of patients with at least one treatment-emergent adverse event (TEAE) did not differ between treatment arms (78.8% for IPE vs. 76.7% for placebo, Fisher’s exact P = .51), nor did total bleeding or bleeding-related serious adverse events (6.9% vs. 8.1%, Fisher’s exact P = .60 and 1.6% vs. 3.2%, Fisher’s exact P = .17, respectively). Among recent ACS patients who were on DAPT at study entry (n = 584), the percentage with at least one treatment-emergent bleeding adverse event was 7.7% in the IPE arm and 9.4% with placebo (Fisher's exact P = .46). No haemorrhagic strokes occurred in either arm. Similar to the overall trial, among recent ACS patients, TEAEs of AF or flutter were higher in the IPE arm than with placebo (7.4% vs. 2.9%, Fisher's exact P = .005), as was the safety endpoint of hospitalizations for AF or flutter (4.8% vs. 1.7%, log-rank P = .01).

Discussion

In REDUCE-IT patients with recent ACS (<12 months before randomization), IPE dramatically reduced ischaemic CV events compared with placebo, apparently more dramatically than in the overall trial (ARR of 9.3%, NNT of 11 vs. ARR 4.8%, NNT of 21).¹ This benefit accrued without increased bleeding, even in patients receiving DAPT. The rates of urgent or emergent revascularization were also reduced, consistent with the results in the overall REDUCE-IT population and in the subgroup with prior MI.^4–8 On the other hand, the risk of AF or flutter was increased with IPE, as previously reported in REDUCE-IT^1,2 and in other trials of omega 3 fatty acids,^9,10 but with no increased risk of stroke. Given the post hoc nature of this analysis and the lack of adjustment for multiplicity, these results should be interpreted with caution and require further confirmation. However, these findings reaffirm the importance of targeting high-risk patients to achieve substantial benefit and the importance of targeting patients with elevated triglycerides early after ACS (within 12 months after the index event).

Conclusion

In this post hoc subgroup analysis of REDUCE-IT, IPE dramatically reduced the risk of ischaemic events in high-risk, statin-treated patients with recent ACS (<12 months), without excess bleeding. This supports initiation of IPE in REDUCE-IT-eligible patients as soon as possible after ACS.

Declarations

Disclosure of Interest

N.S. has no disclosures. D.L.B. serves as the Chair of REDUCE-IT with research funding from Amarin paid to Brigham and Women's Hospital and discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures, Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. M.M. is a scientific advisor for Amarin and a member of the REDUCE-IT steering committee. E.A.B. is a speaker and scientific advisor for Amarin and a member of the REDUCE-IT steering committee, and also a speaker and scientific advisor for Amryt, Inc., Amgen, and Esperion, a scientific advisor for 89Bio, Imunnovant, Novartis, and Pfizer; has received research support from Regeneron. T.A.J. discloses consulting fees from Amgen, Esperion, Novartis, Regeneron, and Sanofi. S.B.K. is an employee and stockholder of Amarin Pharma, Inc. L.J. is a former employee and stockholder of Amarin Pharma, Inc. A.L.P. is an employee and stockholder of Amarin Pharma, Inc. R.T.D. is an employee and stockholder of Amarin Pharma, Inc. J.C.T. discloses grant support from AstraZeneca, Esperion, and Ionis; has received grant support and consulting fees from DalCor and Servier; has received grant support and fees for serving as co-chairman of an executive committee from Pfizer; has received grant support and fees for serving on an executive committee from Sanofi; and holds a minor equity interest in DalCor and a patent (US 9909178 B2) on Dalcetrapib for Therapeutic Use. C.M.B. discloses consulting fees from Arrowhead, AstraZeneca, Eli Lilly, Matinas BioPharma, Merck, Boehringer Ingelheim, Novo Nordisk, Denka Seiken, and Gilead and has received grant support (paid to his institution) and consulting fees from Amarin, Amgen, Esperion, Novartis, Regeneron, Sanofi-Synthelabo, and Akcea. G.S. has received research grants from Amarin, Bayer, Sanofi, Servier. He is or has been a speaker or consultant for Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers-Squibb, Janssen, Kowa, Idorsia, Lexicon, Merck, Novartis, Novo-Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, Servier. He is a senior associate Editor of Circulation.

Data Availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Funding

REDUCE-IT was sponsored by Amarin Pharma, Inc. A complete list of the REDUCE-IT trial investigators can be found at NEJM.org in the supplemental appendix of Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019;380:11-22.

Ethical Approval

The protocol was approved by the relevant health authorities, institutional review boards, and ethics committees.

Pre-registered Clinical Trial Number

The registered clinical trial number is NCT01492361.

Author notes

A complete list of the REDUCE-IT trial investigators can be found at NEJM.org in the supplemental appendix of Bhatt et al.¹