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Cited by 74Fatty Acid Research and HealthLipoproteins and Cardiovascular HealthChronic Kidney Disease and Diabetes

Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL

Open access
Majithia, Arjun, Bhatt, Deepak L., Friedman, Allon N., Miller, Michael, Steg, Ph. Gabriel, Brinton, Eliot A., Jacobson, Terry A., Ketchum, Steven B. +10 more·2021·Circulation
DOI 10.1161/circulationaha.121.055560PMC PMC8614567
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Abstract

Background: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. Methods: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multicenter, double-blind, placebo-controlled trial that randomly assigned statin-treated patients with elevated triglycerides (135–499 mg/dL) who had CVD or diabetes and 1 additional risk factor to treatment with icosapent ethyl (4 g daily) or placebo. Patients from REDUCE-IT were categorized by prespecified estimated glomerular filtration rate (eGFR) categories to analyze the effect of icosapent ethyl on the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Results: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min –1 ·1.73 m –2 (range, 17–123 mL·min –1 ·1.73 m –2 ). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and key secondary composite end points across baseline eGFR categories. Patients with eGFR <60 mL·min –1 ·1.73 m –2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite end point (icosapent ethyl versus placebo, 21.8% versus 28.9%; hazard ratio [HR], 0.71 [95% CI, 0.59–0.85]; P =0.0002) and key secondary composite end point (16.8% versus 22.5%; HR 0.71 [95% CI, 0.57–0.88]; P =0.001). The numeric reduction in cardiovascular death was greatest in the eGFR <60 mL·min –1 ·1.73 m –2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR, 0.70 [95% CI, 0.51–0.95]; P =0.02). Although patients with eGFR <60 mL·min –1 ·1.73 m –2 treated with icosapent ethyl had the highest numeric rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42 [95% CI, 0.86–2.32]; P =0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR, 1.40 [95% CI, 0.90–2.18]; P =0.13), HRs for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories ( P -interaction for atrial fibrillation/flutter=0.92; P -interaction for serious bleeding=0.76). Conclusions: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361

AI snapshot

Written from the paper’s full text.

TL;DR

In REDUCE-IT RENAL, icosapent ethyl 4 g daily reduced the primary and key secondary cardiovascular composite end points across baseline eGFR categories in statin-treated patients with established CVD or diabetes and elevated triglycerides. The largest absolute benefit was seen in patients with eGFR <60 mL·min⁻¹·1.73 m⁻², with consistent relative effects and no significant heterogeneity, although bleeding-related adverse events were more frequent in that subgroup.

Key findings

  • Among 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min⁻¹·1.73 m⁻² (range, 17–123); 1816 (22.2%) had eGFR <60, 4455 (54.5%) had eGFR 60 to <90, and 1902 (23.3%) had eGFR ≥90 mL·min⁻¹·1.73 m⁻².
  • For eGFR <60 mL·min⁻¹·1.73 m⁻², icosapent ethyl reduced the primary composite end point (21.8% versus 28.9%; HR, 0.71 [95% CI, 0.59–0.85]; P=0.0002) and key secondary composite end point (16.8% versus 22.5%; HR, 0.71 [95% CI, 0.57–0.88]; P=0.001), corresponding to a 29% relative and 7.1% absolute reduction in the primary composite and a number needed to treat of 14.
  • Cardiovascular death or nonfatal myocardial infarction was reduced in eGFR <60 (13.9% versus 18.3%; HR, 0.72 [95% CI, 0.57–0.91]; P=0.006) and eGFR 60 to <90 (8.8% versus 11.4%; HR, 0.76 [95% CI, 0.63–0.92]; P=0.004), with numeric reduction in eGFR ≥90.
  • In eGFR <60, bleeding-related disorders were higher with icosapent ethyl (18.0% versus 13.3%; P=0.007), and serious bleeding was 5.4% versus 3.6% (P=0.07); interaction P values were not significant for all bleeding (P=0.68) or serious bleeding (P=0.76). Atrial fibrillation/flutter requiring hospitalization in eGFR <60 was 4.2% versus 3.0% (HR, 1.42 [95% CI, 0.86–2.32]; P=0.17), with no significant interaction (P=0.92).

Methods

  • Prespecified and post hoc analysis of REDUCE-IT, an international, phase 3b, double-blind trial that randomized 8179 statin-treated patients with established CVD or diabetes plus another cardiovascular risk factor, baseline triglycerides 135–500 mg/dL, and LDL cholesterol 41–100 mg/dL to icosapent ethyl 4 g daily or matching placebo.
  • Kidney function was measured by eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation; prespecified eGFR categories were <60, 60 to <90, and ≥90 mL·min⁻¹·1.73 m⁻², with post hoc CKD-stage categories also examined.
  • Efficacy analyses were intention-to-treat; Kaplan-Meier curves and stratified Cox proportional-hazards models estimated hazard ratios and 95% CIs, with interaction terms testing heterogeneity across eGFR categories; testing used a 2-sided significance level of 0.05 without adjustment for multiple comparisons.

Limitations

  • Stated in the paper: REDUCE-IT was not powered specifically for subgroup analyses; patients with creatinine clearance <30 mL·min⁻¹ or needing renal replacement therapy were excluded, so few patients with severe CKD were enrolled and power was limited in that group.
  • Stated in the paper: analyses used prespecified subgroups and post hoc eGFR staging categories, and urine samples were not collected routinely, so microalbuminuria and other specimen-dependent adverse events may be underreported in both treatment arms.
  • Evident from the text: statistical testing was performed without adjustment for multiple comparisons, and the analysis examined multiple eGFR categories and composite end points, which limits inference from subgroup findings.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/circulationaha.121.055560

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

22 of 32 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Despite having a well-controlled low-density lipoprotein cholesterol on statin therapy, patients with elevated triglycerides have significant residual risk for coronary events.

    “Despite having a well-controlled low-density lipoprotein cholesterol on statin therapy, patients with elevated triglycerides have significant residual risk for coronary events.”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [5] Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J. 2015; 36: 774– 776. doi: 10.1093/eurheartj/ehu500 25548060 PMC4471442 source
    • cites [6] Klempfner R Erez A Sagit BZ Goldenberg I Fisman E Kopel E Shlomo N Israel A Tenenbaum A. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease: twenty-two-year follow-up of the Bezafibrate Infarction Prevention Study and Registry. Circ Cardiovasc Qual Outcomes. 2016; 9: 100– 108. doi: 10.1161/CIRCOUTCOMES.115.002104 26957517 source
    • cites [7] Nichols GA Philip S Reynolds K Granowitz CB Fazio S. Increased cardiovascular risk in hypertriglyceridemic patients with statin-controlled LDL cholesterol. J Clin Endocrinol Metab. 2018; 103: 3019– 3027. doi: 10.1210/jc.2018-00470 29850861 source

      The Abstract reports significantly more nonfatal myocardial infarctions and coronary revascularizations in the high-triglyceride group despite statin-controlled LDL cholesterol. The study was limited to patients aged 45 or older with established cardiovascular disease and triglycerides of 200–499 mg/dL; the claim does not retain those population limits. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [8] Toth PP Granowitz C Hull M Liassou D Anderson A Philip S. High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk. J Am Heart Assoc. 2018; 7: e008740. doi: 10.1161/JAHA.118.008740 30371242 PMC6201477 source

      The Methods (Study Populations; page unavailable) describe statin-treated patients with elevated triglycerides, and the Abstract (Methods and Results; page unavailable) reports significantly higher risks of nonfatal myocardial infarction and coronary revascularization than in comparators. However, well-controlled LDL-C was not an inclusion criterion for that outcome analysis. The Discussion describes a separate group with LDL-C ≤100 mg/dL and elevated triglycerides, but does not report its coronary-event risk. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [9] Ganda OP Bhatt DL Mason RP Miller M Boden WE. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol. 2018; 72: 330– 343. doi: 10.1016/j.jacc.2018.04.061 29935936 source
  • Premisecitation

    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.”
    Quote in the paperSubstantial claim6 of 7 sources checked
    • cites [14] Bhatt DL Steg PG Brinton EA Jacobson TA Miller M Tardif JC Ketchum SB Doyle RT Jr Murphy SA Soni PN; REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial. Clin Cardiol. 2017; 40: 138– 148. doi: 10.1002/clc.22692 28294373 PMC5396348 source

      The Methods section identifies the stated primary composite endpoint. But this is a design paper: the Abstract says follow-up will continue until the required events occur. It does not report a median follow-up of 4.9 years or a demonstrated 25% relative risk reduction. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [15] Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle RT Jr Juliano RA Jiao L Granowitz C; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019; 380: 11– 22. doi: 10.1056/NEJMoa1812792 30415628 source
    • cites [16] Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle RT Jr Juliano RA Jiao L Granowitz C; REDUCE-IT Investigators. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019; 73: 2791– 2802. doi: 10.1016/j.jacc.2019.02.032 30898607 source
    • cites [17] Bhatt DL Miller M Brinton EA Jacobson TA Steg PG Ketchum SB Doyle RT Jr Juliano RA Jiao L Granowitz C; REDUCE-IT Investigators. REDUCE-IT USA: results from the 3146 patients randomized in the United States. Circulation. 2020; 141: 367– 375. doi: 10.1161/CIRCULATIONAHA.119.044440 31707829 PMC7004453 source

      The Results (Population Characteristics) give a median follow-up of 4.9 years, and the Methods define the stated primary composite end point. But the Discussion reports a 31% relative risk reduction for that end point in the US cohort, not the claimed 25%; our copy does not substantiate the 25% figure for the overall trial. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [18] Peterson BE Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Juliano RA Jiao L Doyle RT Jr; REDUCE-IT Investigators. Reduction in revascularization with icosapent ethyl: insights from REDUCE-IT revascularization analyses. Circulation. 2021; 143: 33– 44. doi: 10.1161/CIRCULATIONAHA.120.050276 33148016 PMC7752247 source
    • cites [19] Wang X Verma S Mason RP Bhatt DL. The road to approval: a perspective on the role of icosapent ethyl in cardiovascular risk reduction. Curr Diab Rep. 2020; 20: 65. doi: 10.1007/s11892-020-01343-7 33095318 PMC7584545 source

      The Existing Clinical Trials section reports that REDUCE-IT found a 25% relative risk reduction with icosapent ethyl and lists the claimed components of the primary composite endpoint. Our copy does not state the claimed median follow-up of 4.9 years (searched: “median follow-up of 4.9 years” and “4.9”). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [20] Olshansky B Bhatt DL Miller M Steg PG Brinton EA Jacobson TA Ketchum SB Doyle RT Jr Juliano RA Jiao L; REDUCE-IT Investigators. REDUCE-IT INTERIM: accumulation of data across prespecified interim analyses to final results. Eur Heart J Cardiovasc Pharmacother. 2021; 7: e61– e63. doi: 10.1093/ehjcvp/pvaa118 33010162 PMC8141294 source
  • Premisecitation

    Because of gaps in data and negative study results, uncertainty exists over the benefits of applying proven CVD therapy in the general population to the CKD population, especially in patients with advanced kidney disease.

    “However, because of the gaps in data and negative study results, uncertainty exists over the benefits of applying proven CVD therapy in the general population to the CKD population, especially in patients with advanced kidney disease.”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [24] Charytan D Kuntz RE. The exclusion of patients with chronic kidney disease from clinical trials in coronary artery disease. Kidney Int. 2006; 70: 2021– 2030. doi: 10.1038/sj.ki.5001934 17051142 PMC2950017 source
    • cites [25] Baigent C Landray MJ Reith C Emberson J Wheeler DC Tomson C Wanner C Krane V Cass A Craig J; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011; 377: 2181– 2192. doi: 10.1016/S0140-6736(11)60739-3 21663949 PMC3145073 source

      The Introduction says that little was known about CVD prevention in CKD and asks whether LDL-cholesterol-lowering remains effective as renal impairment progresses. The Discussion notes that earlier dialysis and transplant trials had not found significant benefits in their primary outcomes. But the paper addresses LDL-lowering therapy, not proven CVD therapies generally, and its own results support benefits in CKD, including advanced disease. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [26] Wanner C Krane V März W Olschewski M Mann JF Ruf G Ritz E; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005; 353: 238– 248. doi: 10.1056/NEJMoa043545 16034009 source
    • cites [27] Palmer SC Di Micco L Razavian M Craig JC Perkovic V Pellegrini F Copetti M Graziano G Tognoni G Jardine M. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012; 156: 445– 459. doi: 10.7326/0003-4819-156-6-201203200-00007 22431677 source
  • Premiseown data

    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.”
    Quote in the paperSubstantial claim6 of 7 sources checked
    • cites [14] Bhatt DL Steg PG Brinton EA Jacobson TA Miller M Tardif JC Ketchum SB Doyle RT Jr Murphy SA Soni PN; REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial. Clin Cardiol. 2017; 40: 138– 148. doi: 10.1002/clc.22692 28294373 PMC5396348 source

      The Methods section identifies cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke as REDUCE-IT’s key secondary endpoint. But this is a rationale-and-design paper: the Methods say follow-up will continue, and our copy does not report a 26% relative risk reduction or any result for that endpoint. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [15] Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle RT Jr Juliano RA Jiao L Granowitz C; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019; 380: 11– 22. doi: 10.1056/NEJMoa1812792 30415628 source
    • cites [16] Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle RT Jr Juliano RA Jiao L Granowitz C; REDUCE-IT Investigators. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol. 2019; 73: 2791– 2802. doi: 10.1016/j.jacc.2019.02.032 30898607 source
    • cites [17] Bhatt DL Miller M Brinton EA Jacobson TA Steg PG Ketchum SB Doyle RT Jr Juliano RA Jiao L Granowitz C; REDUCE-IT Investigators. REDUCE-IT USA: results from the 3146 patients randomized in the United States. Circulation. 2020; 141: 367– 375. doi: 10.1161/CIRCULATIONAHA.119.044440 31707829 PMC7004453 source

      The Methods identify cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke as the key secondary composite end point. The Discussion reports a 31% relative risk reduction for that end point in the US cohort, not 26%; the Results likewise give a hazard ratio of 0.69. Our copy therefore supports the reduction but not the stated magnitude. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [18] Peterson BE Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Juliano RA Jiao L Doyle RT Jr; REDUCE-IT Investigators. Reduction in revascularization with icosapent ethyl: insights from REDUCE-IT revascularization analyses. Circulation. 2021; 143: 33– 44. doi: 10.1161/CIRCULATIONAHA.120.050276 33148016 PMC7752247 source

      The Introduction reports a 26% relative risk reduction in REDUCE-IT’s key secondary endpoint with icosapent ethyl versus placebo. However, our copy does not define that endpoint as the composite of cardiovascular death, myocardial infarction, and stroke; the Methods define only the five-component primary endpoint. The claimed percentage is supported, but the specified composite is not established by this paper’s text. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [19] Wang X Verma S Mason RP Bhatt DL. The road to approval: a perspective on the role of icosapent ethyl in cardiovascular risk reduction. Curr Diab Rep. 2020; 20: 65. doi: 10.1007/s11892-020-01343-7 33095318 PMC7584545 source

      The Existing Clinical Trials section reports that icosapent ethyl reduced cardiovascular events in REDUCE-IT. It gives a 25% relative risk reduction for a five-component endpoint, however, not a 26% reduction for the three-component composite of cardiovascular death, myocardial infarction, or stroke. No page number is available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [20] Olshansky B Bhatt DL Miller M Steg PG Brinton EA Jacobson TA Ketchum SB Doyle RT Jr Juliano RA Jiao L; REDUCE-IT Investigators. REDUCE-IT INTERIM: accumulation of data across prespecified interim analyses to final results. Eur Heart J Cardiovasc Pharmacother. 2021; 7: e61– e63. doi: 10.1093/ehjcvp/pvaa118 33010162 PMC8141294 source
  • Findingown data

    In patients with eGFR <60 mL·min-1·1.73 m-2, icosapent ethyl reduced the primary composite end point compared with placebo (21.8% vs 28.9%; HR, 0.71 [95% CI, 0.59-0.85]; P=0.0002).

    “Patients with eGFR <60 mL·min–1·1.73 m–2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite end point (icosapent ethyl versus placebo, 21.8% versus 28.9%; HR, 0.71 [95% CI, 0.59–0.85]; P=0.0002)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 14

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CVD remains the leading cause of mortality among patients with CKD.

    “CKD is strongly associated with dyslipidemia, and CVD remains the leading cause of mortality among patients with CKD.25,26,28”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [25] Baigent C Landray MJ Reith C Emberson J Wheeler DC Tomson C Wanner C Krane V Cass A Craig J; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011; 377: 2181– 2192. doi: 10.1016/S0140-6736(11)60739-3 21663949 PMC3145073 source

      The Introduction (page unavailable) says CKD is associated with increased cardiovascular disease risk, supporting the general importance of CVD in this population. It does not say CVD is the leading cause of mortality; the Results (page unavailable) report more non-vascular than vascular deaths in the trial, without ranking individual causes of death. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [26] Wanner C Krane V März W Olschewski M Mann JF Ruf G Ritz E; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005; 353: 238– 248. doi: 10.1056/NEJMoa043545 16034009 source
    • cites [28] Fellström BC Jardine AG Schmieder RE Holdaas H Bannister K Beutler J Chae DW Chevaile A Cobbe SM Grönhagen-Riska C; AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009; 360: 1395– 1407. doi: 10.1056/NEJMoa0810177 19332456 source

      The Patients section (page not available) reports 648 cardiovascular deaths among 1,164 adjudicated deaths in the trial, supporting cardiovascular disease as a major cause of death in patients undergoing hemodialysis. The study concerns patients with end-stage renal disease on hemodialysis; it does not establish that CVD is the leading cause of mortality among all patients with CKD. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    CKD is strongly associated with dyslipidemia.

    “CKD is strongly associated with dyslipidemia, and CVD remains the leading cause of mortality among patients with CKD.25,26,28”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [25] Baigent C Landray MJ Reith C Emberson J Wheeler DC Tomson C Wanner C Krane V Cass A Craig J; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011; 377: 2181– 2192. doi: 10.1016/S0140-6736(11)60739-3 21663949 PMC3145073 source

      The Introduction (page not available) says CKD is associated with increased cardiovascular risk, but does not say it is strongly associated with dyslipidemia. The Results (page not available) compare LDL cholesterol levels among patients with CKD on and off dialysis; they do not establish the claimed CKD–dyslipidemia association. Searches for that association and for lipid abnormalities found no supporting passage in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [26] Wanner C Krane V März W Olschewski M Mann JF Ruf G Ritz E; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005; 353: 238– 248. doi: 10.1056/NEJMoa043545 16034009 source
    • cites [28] Fellström BC Jardine AG Schmieder RE Holdaas H Bannister K Beutler J Chae DW Chevaile A Cobbe SM Grönhagen-Riska C; AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009; 360: 1395– 1407. doi: 10.1056/NEJMoa0810177 19332456 source

      The introduction discusses lipid-lowering therapy in hemodialysis patients and says LDL cholesterol may be low or normal in advanced renal disease; it does not state that CKD is strongly associated with dyslipidemia. The References list a work on dyslipidemia in chronic renal failure, but its title does not establish the claimed association in this paper. No page number is available in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Three studies have examined the relationship between marine derived n-3 fatty acids and cardiovascular outcomes; however, all were performed in patients on hemodialysis and used a less tailored n-3 fatty acid formulation than icosapent ethyl.

    “Three studies have examined the relationship between marine derived n-3 fatty acids and cardiovascular outcomes; however, all were performed in patients on hemodialysis and used a less tailored n-3 fatty acid formulation than icosapent ethyl.29–31”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [29] Svensson M Schmidt EB Jørgensen KA Christensen JH; OPACH Study Group. N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial. Clin J Am Soc Nephrol. 2006; 1: 780– 786. doi: 10.2215/CJN.00630206 17699287 source
    • cites [30] Lok CE Moist L Hemmelgarn BR Tonelli M Vazquez MA Dorval M Oliver M Donnelly S Allon M Stanley K; Fish Oil Inhibition of Stenosis in Hemodialysis Grafts (FISH) Study Group. Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial. JAMA. 2012; 307: 1809– 1816. doi: 10.1001/jama.2012.3473 22550196 PMC4046844 source
    • cites [31] Friedman AN Yu Z Tabbey R Denski C Tamez H Wenger J Thadhani R Li Y Watkins BA. Inverse relationship between long-chain n-3 fatty acids and risk of sudden cardiac death in patients starting hemodialysis. Kidney Int. 2013; 83: 1130– 1135. doi: 10.1038/ki.2013.4 23389417 PMC3655118 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Among patients with diabetes and risk factors, higher event rates were observed in the lowest eGFR group, but a higher absolute risk reduction was not consistently observed.

    “Among patients with diabetes and risk factors, higher event rates were observed in the lowest eGFR group, but a higher absolute risk reduction was not consistently observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At a median follow-up of 4.9 years, both the primary and secondary composite end points were significantly reduced among patients treated with icosapent ethyl.

    “At a median follow-up of 4.9 years, both the primary and secondary composite end points were significantly reduced among patients treated with icosapent ethyl.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The relative risk for atrial fibrillation among icosapent ethyl-treated patients was similar among eGFR categories, with no significant interaction (P-interaction=0.92).

    “The relative risk for atrial fibrillation among icosapent ethyl–treated patients was similar among eGFR categories, with no significant interaction observed (P-interaction=0.92; Figure S7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Relative risks for all and serious bleeding were similar across eGFR categories, with no significant interaction.

    “Overall, bleeding rates were higher with decreasing eGFR, but the relative risks for all and serious bleeding were similar across eGFR categories, with no significant interaction observed.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Of the patients, 1816 (22.2%) had eGFR <60 mL·min-1·1.73 m-2, 4455 (54.5%) had eGFR 60 to <90 mL·min-1·1.73 m-2, and 1902 (23.3%) had eGFR ≥90 mL·min-1·1.73 m-2.

    “Of the patients, 1816 (22.2%) had eGFR <60 mL·min–1·1.73 m–2, 4455 (54.5%) had eGFR 60 to <90 mL·min–1·1.73 m–2, and 1902 (23.3%) had eGFR ≥90 mL·min–1·1.73 m–2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among patients treated with icosapent ethyl with eGFR <60 mL·min-1·1.73 m-2, there was a 29% relative and 7.1% absolute reduction in the primary composite end point, corresponding to a number needed to treat of 14.

    “Among patients treated with icosapent ethyl with eGFR <60 mL·min–1·1.73 m–2, there was a 29% relative and 7.1% absolute reduction in the primary composite end point, corresponding to a number needed to treat of 14.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Microalbuminuria was reported at low rates, more commonly with placebo (14 versus 3; P=0.01).

    “Microalbuminuria was reported at low rates, more commonly with placebo (14 versus 3; P=0.01), and expressed no clear trend across eGFR subgroup.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Absolute and relative risk differences for atrial fibrillation/flutter were similar to those observed in other eGFR subgroups with no significant interaction.

    “Atrial fibrillation/flutter event rates were higher in the lowest eGFR group, although absolute and relative risk differences were similar to those observed in other eGFR subgroups with no significant interaction observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was an increase in total bleeding events with icosapent ethyl without an increase in serious central nervous system or gastrointestinal bleeding.

    “A safety profile similar to the full cohort was observed for icosapent ethyl compared with placebo across eGFR subgroups, including an increase in total bleeding events without an increase in serious central nervous system or gastrointestinal bleeding, and an increase in the rates of atrial fibrillation or atrial flutter.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Among the 8179 REDUCE-IT patients, the median baseline eGFR was 75 mL·min-1·1.73 m-2 (range, 17-123 mL·min-1·1.73 m-2).

    “Among the 8179 REDUCE-IT patients, the median baseline eGFR was 75 mL·min–1·1.73 m–2 (range, 17–123 mL·min–1·1.73 m–2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Hazard ratios for all bleeding and serious bleeding events were similar regardless of eGFR cutoff, with no significant interaction (P interactions for all bleeding=0.68 and serious bleeding=0.76).

    “However, HRs for all bleeding and serious bleeding events were similar regardless of eGFR cutoff, with no significant interaction observed (P interactions for all bleeding=0.68 and serious bleeding=0.76; Figure S7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Treatment with icosapent ethyl has been shown to significantly reduce cardiovascular events and mortality in this patient population.

    “Treatment with icosapent ethyl has been shown to significantly reduce cardiovascular events and mortality in this patient population.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The REDUCE-IT study was not powered specifically for subgroup analyses.

    “The REDUCE-IT study was not powered specifically for subgroup analyses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    There were no significant between-group differences in baseline low-density lipoprotein cholesterol or triglyceride levels.

    “There were no significant between-group differences in baseline low-density lipoprotein cholesterol or triglyceride levels.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Urine samples were not collected routinely in REDUCE-IT.

    “Last, urine samples were not collected routinely in REDUCE-IT.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These benefits extend to significant reductions in myocardial infarction and cardiovascular death.

    “These benefits extend to significant reductions in myocardial infarction and cardiovascular death.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All efficacy analyses were performed according to the intention-to-treat principle.

    “All efficacy analyses were performed according to the intention-to-treat principle.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    At baseline, median low-density lipoprotein cholesterol was similar among icosapent ethyl- and placebo-treated patients (74 versus 76 mg/dL).

    “At baseline, median low-density lipoprotein cholesterol was similar among icosapent ethyl- and placebo-treated patients (74 versus 76 mg/dL).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    An independent committee blinded to treatment performed end point adjudication.

    “An independent committee blinded to treatment performed end point adjudication.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Atrial fibrillation/flutter requiring hospitalization was an adjudicated end point.

    “Atrial fibrillation/flutter requiring hospitalization was an adjudicated end point, and rates of positively adjudicated atrial fibrillation/flutter were higher in the eGFR <60 mL·min–1·1.73 m–2 subgroup, although absolute risk differences were similar across eGFR categories (icosapent ethyl: 4.2%; placebo 3.0%; HR, 1.42 [95% CI, 0.86–2.32]; P=0.17; Figure S7).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Statistical testing was based on a 2-sided significance level of 0.05 without adjustment for multiple comparisons.

    “Statistical testing was based on a 2-sided significance level of 0.05 without adjustment for multiple comparisons.”
    Quote in the paperNot a substantial claim
24 of 24

  • The paper relies on this without support.

    Commonly used cardiovascular medications that treat dyslipidemia may be ineffective among patients with severe CKD.

    “Commonly used cardiovascular medications that treat dyslipidemia may be ineffective among patients with severe CKD.”

  • The paper relies on this without support.

    The benefit of statin-based therapy decreases as eGFR declines.

    “The benefit of statin-based therapy decreases as eGFR declines.”

  • The paper relies on this without support.

    Limited data exist on the clinical benefit of nonstatin medications, such as niacin, among patients with CKD.

    “Limited data exist on the clinical benefit of nonstatin medications, such as niacin, among patients with CKD.”

  • The paper relies on this without support.

    Both gemfibrozil and fenofibrate are renally cleared so they either require dose reduction or should be avoided depending on the severity of CKD.

    “Both gemfibrozil and fenofibrate are renally cleared so they either require dose reduction or should be avoided depending on the severity of CKD.”

  • The paper relies on this without support.

    The dyslipidemia of CKD is characterized primarily by hypertriglyceridemia and reduced levels of high-density lipoprotein cholesterol.

    “The dyslipidemia of CKD is characterized primarily by hypertriglyceridemia and reduced levels of high-density lipoprotein cholesterol.”

  • The paper relies on this without support.

    Therapies targeting triglyceride reduction may modify cardiovascular risk.

    “Therefore, therapies targeting triglyceride reduction may modify cardiovascular risk.”
6 of 6

Cites

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Authors
Majithia, 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., Doyle, R. T., Granowitz, C., Budoff, M., Preston Mason, R., Tardif, J.-C., Boden, W. E., Ballantyne, C. M., & on behalf of the REDUCE-IT Investigators
Affiliations
  • Lahey Hospital and Medical Center (US)
  • Brigham and Women's Hospital (US)
  • Indiana University Indianapolis (US)
  • University of Maryland, Baltimore (US)
  • Université de Paris, FACT (French Alliance for Cardiovascular Trials), Assistance Publique–Hôpitaux de Paris, Hôpital Bichat, INSERM Unité 1148, France (P.G.S.).
  • Utah Lipid Center, Salt Lake City (E.A.B.).
  • Emory University (US)
  • Amarin (United States) (US)
  • Harbor–UCLA Medical Center (US)
  • Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (D.L.B., R.P.M.).
  • Montreal Heart Institute (CA)
  • Boston Medical Center (US)
  • Baylor College of Medicine (US)
Corresponding author
Bhatt, Deepak L.
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-11-30
Volume
144
Issue
22
Pages
1750-1759
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.121.055560
PMC
PMC8614567
OpenAlex
W3208705919
Cited by
74
References
31
Citations by year
2026: 14 · 2025: 17 · 2024: 10 · 2023: 17 · 2022: 15 · 2021: 1
FWCI
5.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Circulation (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
  • Brigham and Women's Hospital
  • Amarin Corporation
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
icosapent ethyl, chronic kidney disease, estimated glomerular filtration rate, cardiovascular events, cardiovascular mortality, myocardial infarction, stroke, triglyceride elevation, statin-treated patients, diabetes mellitus, cardiovascular disease, REDUCE-IT trial, renal safety, omega-3 fatty acids, cardiovascular risk reduction, renal function preservation
MeSH terms
Aged, Cardiovascular Diseases, Double-Blind Method, Female, Glomerular Filtration Rate, Humans, Male, Middle Aged, Eicosapentaenoic Acid, Renal Insufficiency, Chronic

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

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