This commentary refers to ‘A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs’, by T. Doi et al., https://doi.org/10.1093/eurheartj/ehab555 and the discussion piece ‘Mineral oil and icosapent ethyl may jointly explain the between arm difference of cardiovascular risk in REDUCE-IT’ by T. Doi et al., https://doi.org/10.1093/eurheartj/ehab764.
We have read with interest the analysis trying to emulate the results of the REDUCE IT and STRENGTH trials using the Copenhagen observational database.1 We wish to share several concerns with the authors regarding their assumptions. The analysis assumes that lipid profile differences account for treatment and placebo effects when there are potential myriad other intermediate/surrogate markers. It examined relatively small differences in certain biomarkers, but did not factor in the very large change in eicosapentaenoic acid (EPA) levels that occurred in REDUCE-IT. The latter likely explains the bulk of benefit seen in that trial due to downstream effects of EPA that basic scientists are still unravelling.2 Our main concern is that such an analysis attempting to correlate clinical benefits of EPA to changes in selected surrogate biomarkers can miss major causal known or unknown pathways. The recent demonstration of major cardiovascular benefits of SGLT2 inhibitors despite a moderate glucose-lowering effect exemplifies the potential disconnect between selected surrogate biomarkers and outcomes.
In addition, the authors regrettably did not have access to changes in lipid and high sensitivity C-reactive protein (hs-CRP) profiles during follow-up in their study, so instead they compared differences in baseline lipid and hs-CRP profiles and correlated them to differences in risk. Unfortunately, this is problematic because there are major confounding differences between patients compared on the basis of their baseline characteristics (in contrast to what happens in a randomized trial where all things are equal at randomization). In addition, the effect of differences in biomarkers on risk is exaggerated because differences in baseline risk reflect lifetime exposure to different levels of LDL, apo B, triglycerides, and hs-CRP up to enrolment, as opposed to short-term changes, as would be seen in a prospective trial.
The issue of placebo choice and changes in biomarkers has been thoroughly reviewed by the US FDA, Health Canada, and the European Medicines Agency, who all concluded that any theoretical effect of placebo choice on the 25% risk reduction seen in REDUCE-IT would have been very small.3 In addition, icosapent ethyl has also been studied in two other randomized trials which did not use any placebo and still showed clear benefit—JELIS with a significant 19% reduction in clinical endpoints and CHERRY with a significant benefit on intravascular ultrasound endpoints.4 , 5 While clinical events are far more important than any biomarker changes, for those who are concerned about such issues, data from PREPARE-IT 1 will provide another opportunity to assess any effects of pharmaceutical grade mineral oil placebo on hs-CRP levels, including with use of a higher loading dose of placebo in that trial.
The totality of evidence of randomized clinical trials (with and without use of a placebo), imaging data, observational data, and basic science data all support an important biological and clinical effect of EPA. As the authors themselves state,1 the available data ‘support the European guideline recommendations to consider use of omega-3 fatty acids (icosapent ethyl 2 × 2 g/day) in combination with a statin in high-risk patients with triglyceride levels between 1.5 and 5.6 mmol/L (135–499 mg/dL) despite statin treatment’.
Conflict of interest: G.S. discloses the following relationships: research grants: Amarin, Bayer, Sanofi, and Servier; Clinical Trials (Steering committee, CEC, DSMB): Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Novartis, Pfizer, Sanofi, Servier; consulting or speaking: Amgen, BMS/Myokardia, Novo-Nordisk, Regeneron; and senior associate editor at Circulation. D.L.B. discloses the following relationships—advisory board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair: Inaugural Chair, American Heart Association Quality Oversight Committee; data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), 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), Novartis, Population Health Research Institute; honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; chair, ACC Accreditation Oversight Committee), 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), 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, 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); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), VA CART Research and Publications Committee (chair); research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, Svelte; trustee: American College of Cardiology; and unfunded research: FlowCo, Merck, Takeda.
Contributor Information
Ph Gabriel Steg, Université de Paris, FACT (French Alliance for Cardiovascular Trials), Assistance Publique-Hôpitaux de Paris and INSERM U1148, Hôpital Bichat, 46 rue Henri Huchard, Paris 75018, France.
Deepak L Bhatt, Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
References
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