REDUCE-IT INTERIM: accumulation of data across prespecified interim analyses to final results
Open accessAbstract
REDUCE-IT was designed as a randomized, placebo-controlled, cardiovascular outcomes trial of patients treated with statins, who had controlled low-density lipoprotein cholesterol, but persistently elevated triglycerides, along with overt presence of or high risk for cardiovascular disease.1 Participants across 11 countries were randomized to receive icosapent ethyl, a highly purified form of eicosapentaenoic acid, 2 g twice daily or placebo and followed for a median of 4.9 years (maximum 6.2 years). The primary endpoint was time from randomization to first occurrence of a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The key secondary endpoint was time from randomization to first occurrence of a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Icosapent ethyl was associated with marked reductions in primary and key secondary endpoints with a number needed to treat of 21 for the primary composite endpoint and 28 for the key secondary endpoint.2 The relative risk reduction for the primary endpoint was 25% (P = 0.00000001) and for the key secondary endpoint was 26% (P = 0.0000006), with an absolute risk reduction of the primary endpoint of 4.8% and key secondary endpoint of 3.6%.2 There was a 32% relative reduction in total (first and recurrent) ischaemic events.3 REDUCE-IT was an event-driven trial of 8179 patients. A total of 1612 primary endpoint events were targeted to occur with a projected 90% power to detect a 15% relative risk reduction.1 The independent Data Safety and Monitoring Committee (DMC) were to perform prespecified, unblinded interim analyses1 at ∼60% of events (April 2016) with a 2.9 year median follow-up and 953 first events and at ∼80% of events (April 2017) with 3.7 year median follow-up and 1218 events. The final analysis on 6 September 2018 was at 4.9 years median study follow-up with 1606 first events.2,3 An interim statistical analysis plan guided study continuation recommendations according to a prespecified decision-making process including assessment of safety, treatment arm performance, primary composite endpoint formal analysis, and internal robustness analysis with no futility stopping boundary requirements. The DMC included two physicians, a PhD statistician, and a non-voting independent statistician. Independent statistical support was provided by Cytel, Inc. Prior to DMC interim analysis study continuation recommendations, the DMC discussed the importance of a more mature data set to support robustness of final efficacy and safety findings. The steering committee, sponsor, and clinical endpoint committee were blinded to treatment throughout the trial prior to the final database lock. In REDUCE-IT, primary and key secondary endpoints achieved statistical significance at both interim analyses. This persisted at the final analysis, surpassing the final two-sided alpha of 0.0437 adjusted to account for interim analyses. Clarity of efficacy findings across endpoints and subgroups improved steadily with time and greater number of events. Overall safety was consistent across interim and final analyses. Stopping for overwhelming efficacy was discussed by the DMC at each interim analysis. The DMC considered historical examples of failed cardiovascular outcome studies for triglyceride lowering and mixed omega-3 therapies, reflected on potential for overestimating final demonstrated benefit using an incomplete data set, and weighed societal impacts for further safety and efficacy data sets relative to patient access.4 Considering accumulation of data at interim analyses 1 and 2 and in the final analysis, icosapent ethyl was consistently superior to placebo regarding primary and key secondary endpoints. For the primary endpoint, for interim analysis 1, the hazard ratio (HR) was 0.77 [95% confidence interval (CI) 0.68–0.87; P = 0.00005]; for interim analysis 2, the HR was 0.77 (95% CI 0.69–0.87; P = 0.0000008), and for the final analysis, the HR was 0.75 (95% CI 0.68–0.83; P = 0.00000001). For key secondary endpoints, for interim analysis 1, the HR was 0.71 (95% CI 0.60–0.83; P = 0.00005), for interim analysis 2, the HR was 0.72 (95% CI 0.62–0.83; P = 0.000009), and for the final analysis, the HR was 0.74 (95% CI 0.65–0.83; P = 0.0000006). The probability that results of the first and second interim analyses would ultimately become non-significant in the final analysis was considered by the DMC to be highly unlikely. In the continuous landmark analysis of the primary composite endpoint, the HR was below unity at all timepoints, with consistent and statistically significant outcome measures starting at 21 months (Figure 1A). Similarly, a continuous landmark analysis of the key secondary endpoint showed consistent and statistically significant advantage of icosapent ethyl vs. placebo starting at 25 months (Figure 1B). (A) Rate of the prim
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Patients treated with icosapent ethyl had a 26% relative risk reduction in the composite of cardiovascular death, myocardial infarction, or stroke.
“The study further demonstrated that patients treated with icosapent ethyl had a 26% relative risk reduction in the composite of cardiovascular death, myocardial infarction, or stroke.”
From Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL (2021) · cites this paper as [20]
After a median follow-up of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite end point of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina.
“After a median follow-up period of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite end point of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina.”
From Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL (2021) · cites this paper as [20]
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Cites
Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia
Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1812792 · Cited by 3,317 · see citing works
Self-citationEffects of Icosapent Ethyl on Total Ischemic Events
Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.02.032 · Cited by 259 · see citing works
Self-citationBhatt, D. L., Steg, P. G., Brinton, E. A., Jacobson, T. A., Miller, M., Tardif, J., Ketchum, S. B., Doyle, R. T., Murphy, S. A., Soni, P. N., et al. (2017) · Clinical Cardiology · doi:10.1002/clc.22692 · Cited by 183 · see citing works
Self-citationREDUCE-IT USA: Results From the 3146 Patients Randomized in the United States
Bhatt, D. L., Miller, M., Brinton, E. A., Jacobson, T. A., Steg, P. G., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.044440 · Cited by 136 · see citing works
Self-citationRisks of Overinterpreting Interim Data
Jolly, S. S., Gao, P., Cairns, J. A., Yusuf, S., Bhatt, D. L., Wyse, D. G., Wells, G. A., & Džavík, V. (2018) · Circulation · doi:10.1161/circulationaha.117.030656 · Cited by 4 · see citing works
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Role of Omega-3 Fatty Acids in Cardiovascular Disease: the Debate Continues
Sherratt, S. C. R., Libby, P., Budoff, M. J., Bhatt, D. L., & Mason, R. P. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01075-x · Cited by 143 · see citing works
Self-citationMajithia, A., Bhatt, D. L., Friedman, A. N., Miller, M., Steg, P. G., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Juliano, R. A., Jiao, L., et al. (2021) · Circulation · doi:10.1161/circulationaha.121.055560 · Cited by 74 · see citing works
Self-citationDo patients benefit from omega-3 fatty acids?
Sherratt, S. C. R., Mason, R. P., Libby, P., Steg, P. G., & Bhatt, D. L. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad188 · Cited by 71 · see citing works
Self-citationGaba, P., Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Juliano, R. A., Jiao, L., Doyle, R. T., et al. (2022) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2022.02.035 · Cited by 61 · see citing works
Self-citationPeterson, B. E., Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Juliano, R. A., Jiao, L., Doyle, R. T., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.050276 · Cited by 57 · see citing works
Self-citationPeterson, B. E., Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Juliano, R. A., Jiao, L., Doyle, R. T., et al. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.121.022937 · Cited by 46 · see citing works
Self-citationComparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT
Gaba, P., Bhatt, D. L., Giugliano, R. P., Steg, P. G., Miller, M. J., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Juliano, R. A., Jiao, L., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.08.009 · Cited by 38 · see citing works
Self-citationOmega-3 fatty acids for cardiovascular event lowering
Kaur, G., Mason, R. P., Steg, P. G., & Bhatt, D. L. (2024) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwae003 · Cited by 40 · see citing works
Self-citationOlshansky, B., Bhatt, D. L., Miller, M., Steg, P. G., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., et al. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.121.026756 · Cited by 29 · see citing works
Self-citationOmega-3 and cardiovascular prevention – Is this still a choice?
Ruscica, M., Sirtori, C. R., Carugo, S., Calder, P. C., & Corsini, A. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106342 · Cited by 28 · see citing works
Miller, M. J., Tokgözoğlu, L. S., Parhofer, K. G., Handelsman, Y., Leiter, L. A., Landmesser, U., Brinton, E. A., & Catapano, A. L. (2022) · Expert Review of Cardiovascular Therapy · doi:10.1080/14779072.2022.2103541 · Cited by 25 · see citing works
Self-citationBhatt, R. D., Libby, P., Verma, S., Mason, R. P., & Bhatt, D. L. (2021) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2021.08.003 · Cited by 22 · see citing works
Self-citationGaba, P., Bhatt, D. L., Mason, R. P., Miller, M. J., Verma, S., Steg, P. G., & Boden, W. E. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.05.067 · Cited by 20 · see citing works
Self-citationQuantitative imaging biomarkers of coronary plaque morphology: insights from EVAPORATE
Buckler, A. J., Doros, G. D., Kinninger, A., Lakshmanan, S., Le, V. T., Libby, P., May, H. T., Muhlestein, J. B., Nelson, J. R., Nicolaou, A., et al. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1204071 · Cited by 10 · see citing works
Self-citationDyslipidaemias and cardiovascular diseases: beyond cholesterol and atherosclerotic plaques
Crea, F. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa889 · Cited by 5 · see citing works
Benefit of icosapent ethyl across types and sizes of myocardial infarction in REDUCE-IT
Gurevitz, C., Bhatt, D. L., Giugliano, R. P., Steg, P. G., Miller, M. J., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Pineda, A. L., Doyle, R. T., et al. (2025) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwaf602 · Cited by 3 · see citing works
Self-citationSingh, N., Dove, E., & Bhatt, D. L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-88286-6.00019-4 · Cited by 2 · see citing works
Self-citationSubstantial Impact of Eicosapentaenoic Acid on Cardiovascular Outcomes in the REDUCE-IT Trial
Bhatt, D. L. (2022) · CardioMetabolic Syndrome Journal · doi:10.51789/cmsj.2022.2.e3 · Cited by 1 · see citing works
Self-citationImproved group sequential Holm procedures for testing multiple correlated hypotheses over time
Öhrn, F., Niewczas, J., & Burman, C. (2021) · Journal of Biopharmaceutical Statistics · doi:10.1080/10543406.2021.1979574 · Cited by 1 · see citing works
Icosapent ethyl reduces CVD risk in cardiovascular-kidney-metabolic syndrome: REDUCE-IT CKM
Miller, M., Bhatt, D. L., Brinton, E. A., Jacobson, T. A., Steg, P. G., Ketchum, S. B., Pineda, A. L., Tardif, J.-C., & Ballantyne, C. M. (2026) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2025.101387
“As such, the current study supports IPE as a potential therapeutic strategy for CKM patients beyond traditional standard of care measures as outlined in the recent AHA Scientific Statement [3] and extends its potential utility outside other patient groups at high cardiovascular risk ([7,19 – 27]).”
Self-citationWhat Types of Formal Interim Analyses Does the DMC Review?
Liu, L., & Mehta, C. R. (2023) · Springer eBooks · doi:10.1007/978-3-031-28760-2_15
Self-citationWhat Are the Legal and Financial Aspects of a DMC?
Kerr, D., & Rawat, N. K. (2023) · Springer eBooks · doi:10.1007/978-3-031-28760-2_5
What Types of Efficacy Outputs Does the DMC Receive?
Kerr, D., & Rawat, N. K. (2023) · Springer eBooks · doi:10.1007/978-3-031-28760-2_12
Is a DMC Required? What Other Groups Are Involved?
Kerr, D., & Rawat, N. K. (2023) · Springer eBooks · doi:10.1007/978-3-031-28760-2_3
Cequier, A. R., & Zamorano, J. L. (2023) · Revista Española de Cardiología Suplementos · doi:10.1016/s1131-3587(23)00012-2
- Authors
- Olshansky, B., Bhatt, D. L., Miller, M., Steg, P. G., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle Jr, R. T., Juliano, R. A., Jiao, L., Granowitz, C., Tardif, J.-C., Mehta, C., Mukherjee, R., Ballantyne, C. M., Chung, M. K., & the REDUCE-IT Investigators
- Affiliations
- University of Iowa Hospitals and Clinics (US)
- Brigham and Women's Hospital (US)
- University of Maryland, Baltimore (US)
- French Alliance for Cardiovascular Trials, Hôpital Bichat, Assistance Publique, - Hôpitaux de Paris, 46 rue Henri Huchard, Paris 75018, France
- Utah Lipid Center, 421 Wakara Way, Salt Lake City, UT 84108, USA
- Emory University (US)
- Amarin (United States) (US)
- Amarin Pharma, Inc., Inc. 440 Route 22, Bridgewater, NJ 08807, USA
- Montreal Heart Institute (CA)
- Cytel (United States) (US)
- Houston Methodist (US)
- Cleveland Clinic (US)
- Corresponding author
- Olshansky, Brian
- ORCID
- Venue
- European Heart Journal - Cardiovascular Pharmacotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-10-03
- Volume
- 7
- Issue
- 3
- Pages
- e61-e63
- ISSN
- 2055-6837 (ISSN-L)
- 2055-6845
- PMC
- PMC8141294
- OpenAlex
- W3091209026
- Cited by
- 25
- References
- 5
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 9 · 2022: 7 · 2021: 4 · 2020: 2
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Heart Journal - Cardiovascular Pharmacotherapy (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- Gilead Sciences
- Emory University
- Cleveland Clinic
- Case Western Reserve University
- CSL Behring
- Boston Scientific Corporation
- Medicure
- Regeneron Pharmaceuticals
- Ironwood Pharmaceuticals, Incorporated
- Amarin Corporation
- Medicines Company
- Belvoir Media Group
- Eisai
- Novo Nordisk
- Servier
- Institut de Cardiologie de Montréal
- Idorsia Pharmaceuticals
- Esperion Therapeutics
- St. Jude Medical
- School of Medicine, Emory University
- Amarin Pharma
- Houston Methodist Research Institute
- Duke Clinical Research Institute
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- REDUCE-IT trial, icosapent ethyl, eicosapentaenoic acid, omega-3 fatty acids, triglyceride-rich lipoproteins, cardiovascular outcomes, interim analysis, primary endpoint, myocardial infarction, stroke, coronary revascularization
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