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Cited by 4,487Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismAcute Myocardial Infarction Research

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes

Open access
Cannon, Christopher P., Blazing, Michael A., Giugliano, Robert P., McCagg, Amy, White, Jennifer A., Theroux, Pierre, Darius, Harald, Lewis, Basil S. +13 more·2015·New England Journal of Medicine
DOI 10.1056/nejmoa1410489
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Abstract

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).

Integrity signals

Registry

Crossref · 10.1056/nejmoa1410489

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

12 of 28 cited sources checked · 7 supported · 1 flagged · accuracy not yet measured

  • Findingown data

    The rate of major vascular events as defined by the CTT collaborators was significantly lower in the simvastatin-ezetimibe group (difference, 2.2 percentage points; hazard ratio, 0.928; P=0.007).

    “The rate of major vascular events as defined by the CTT collaborators 3,4 (a composite of death from coronary heart disease, myocardial infarction, stroke, or coronary revascularization 30 days or more after randomization) was also significantly lower in the simvastatin-ezetimibe group (difference, 2.2 percentage points; hazard ratio, 0.928; P = 0.007).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] source
    • cites [4] source

      The Study eligibility and outcomes section (page unavailable) defines a major vascular event as the first major coronary event, coronary revascularisation, or stroke, matching the cited composite. But the sentence makes the 30-day cutoff sound universal: in acute-coronary-syndrome trials, the paper included revascularisation for recurrent ischaemia or procedures more than 30 days after randomisation, depending on the trial. The citation is attached to the CTT definition, not to the simvastatin–ezetimibe results. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The higher rate of hemorrhagic stroke with simvastatin-ezetimibe is similar to that seen with statin therapy as compared with placebo.

    “a finding similar to that seen with statin therapy as compared with placebo.3,4”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [3] source
    • cites [4] source
  • Findingown data

    In IMPROVE-IT, using the CTT approach and end point, there was a between-group difference in LDL cholesterol levels (with imputation for missing values) of 12.8 mg per deciliter.

    “we observed a between-group difference in LDL cholesterol levels (with imputation for missing values) of 12.8 mg per deciliter”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] source
    • cites [4] source
  • Interpretationcitation

    The consistency with expectations from the CTT analysis, in which a different class of drug was used, provides further evidence for a relationship between lipid lowering and improved outcomes.

    “However, the consistency with expectations from the CTT analysis, in which a different class of drug was used, provides further evidence for a relationship between lipid lowering and improved outcomes.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] source
    • cites [4] source
  • Findingown data

    In IMPROVE-IT, using the CTT approach and end point, there was a proportional 7.2% lower rate of major vascular events.

    “and a proportional 7.2% lower rate of major vascular events”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] source
    • cites [4] source

      The Study eligibility and outcomes section defines the CTT major vascular event endpoint, and the Results describe its analysis of first-event rates. Our copy does not report IMPROVE-IT or a 7.2% reduction in that trial; its Results instead report reductions across the trials in this meta-analysis. Page numbers were not available in the supplied passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 24
  • The quote only partly states this claim. 1

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

    Study design and conductcitation

    Randomization was stratified according to prior use of lipid-lowering therapy, type of acute coronary syndrome, and enrollment in the concurrent EARLY ACS trial.

    “Randomization was stratified according to prior use of lipid-lowering therapy, type of acute coronary syndrome, and status with respect to enrollment in the concurrent Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial.25”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] source

      The Study Procedures section (page unavailable) says randomization was blocked by study center and stratified by investigators’ intention to administer early clopidogrel, not by the three factors claimed. The paper identifies itself as the EARLY ACS trial, rather than a separate trial conducted concurrently with it. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) protein, thereby reducing absorption of cholesterol from the intestine.

    “Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) protein, thereby reducing absorption of cholesterol from the intestine.15,16”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [15] source
    • cites [16] source

      The Introduction says ezetimibe prevents absorption of dietary and biliary cholesterol across the intestinal wall. It does not identify NPC1L1 as ezetimibe’s target; searches for NPC1L1 and the molecular target found no supporting passage in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Polymorphisms affecting NPC1L1 are associated with both lower levels of LDL cholesterol and a lower risk of cardiovascular events.

    “Polymorphisms affecting NPC1L1 are associated with both lower levels of LDL cholesterol and a lower risk of cardiovascular events.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] source

      The Abstract Results and Discussion report that carriers of rare, inactivating NPC1L1 mutations had lower LDL cholesterol and a lower risk of coronary heart disease. The claim is broader: the paper does not establish these associations for NPC1L1 polymorphisms generally or for cardiovascular events beyond coronary heart disease. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    According to practice guidelines in place at the time of patient enrollment in IMPROVE-IT, treatment of hypercholesterolemia was based on lowering LDL cholesterol to target levels, which were set on the basis of a patient's risk of cardiovascular events.

    “According to practice guidelines in place at the time of patient enrollment in IMPROVE-IT, treatment of hypercholesterolemia was based on lowering LDL cholesterol to target levels, 20,21 which were set on the basis of a patient's risk of cardiovascular events.”
    Quote in the paperNot a substantial claim2 of 2 sources checked

  • May combine two claims.

    Findingown data

    The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group and 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016).

    “The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant between-group differences were seen in the percentage of patients with alanine aminotransferase elevations exceeding three times the upper limit of normal or in rates of gallbladder-related adverse events, cholecystectomy, muscle-related adverse events, or new, relapsing, or worsening cancer.

    “No significant between-group differences were seen in the percentage of patients who had elevations in alanine aminotransferase levels that exceeded three times the upper limit of the normal range or in the rates of gallbladder-related adverse events, cholecystectomy, muscle-related adverse events, or new, relapsing, or worsening cancer (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 1 year, levels of total cholesterol, triglycerides, non-HDL cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein were all significantly lower in the simvastatin-ezetimibe group than in the simvastatin-monotherapy group.

    “At 1 year, levels of total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein were all significantly lower in the simvastatin-ezetimibe group than in the simvastatin-monotherapy group (Table S1 in the Supplementary Appendix).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The benefit appeared to be particularly pronounced in patients with diabetes mellitus and in patients 75 years of age or older.

    “The benefit appeared to be particularly pronounced in patients with diabetes mellitus and in patients 75 years of age or older.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The rates of death from cardiovascular causes and from any cause were similar in the two groups.

    “The rates of death from cardiovascular causes and from any cause were similar in the two groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was a nonsignificantly higher risk of hemorrhagic stroke with simvastatin-ezetimibe than with simvastatin monotherapy (difference, 0.2 percentage points; hazard ratio, 1.38; P=0.11), although the number of hemorrhagic strokes was low.

    “There was a nonsignificantly higher risk of hemorrhagic stroke with simvastatin-ezetimibe than with simvastatin monotherapy (difference, 0.2 percentage points; hazard ratio, 1.38; P = 0.11), although the number of hemorrhagic strokes was low.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Discontinuation of study medication owing to an adverse event occurred in 10.1% of patients in the simvastatin-monotherapy group and 10.6% of those in the simvastatin-ezetimibe group.

    “Discontinuation of study medication owing to an adverse event occurred in 10.1% of the patients in the simvastatin-monotherapy group and in 10.6% of those in the simvastatin-ezetimibe group.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    A greater proportion of patients in the simvastatin-ezetimibe group than in the simvastatin-monotherapy group achieved the dual goal of an LDL cholesterol level of less than 70 mg per deciliter and a high-sensitivity C-reactive protein level of less than 2.0 at 1 month (50.6% vs. 30.5%).

    “level of less than 2.0 at 1 month (50.6% vs. 30.5%)(Table S2 in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In IMPROVE-IT, no between-group differences in cardiovascular mortality or in the rate of death from any cause were observed.

    “No between-group differences in cardiovascular mortality or in the rate of death from any cause were anticipated or observed in IMPROVE-IT”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In IMPROVE-IT, significant reductions were observed in the rates of myocardial infarction and ischemic stroke.

    “However, significant reductions were observed in the rates of myocardial infarction and ischemic stroke.”
    Quote in the paperSubstantial claim

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

    Findingown data

    There was a higher use of the 80-mg simvastatin dose in the simvastatin-monotherapy group than in the simvastatin-ezetimibe group.

    “albeit with a higher use of the 80-mg simvastatin dose in the simvastatinmonotherapy group than in the simvastatinezetimibe group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In IMPROVE-IT, the treatment period extended for an average of 6 years, and the differences between the two treatment groups emerged after about 1 year, by which time most of the data were from patients in the chronic phase of their disease.

    “However, the treatment period extended for an average of 6 years, and the differences between the two treatment groups emerged after about 1 year, by which time most of the data were from patients in the chronic phase of their disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In IMPROVE-IT, 42% of the patients discontinued the study medication for any reason prematurely, with an equal proportion in the two groups.

    “Finally, 42% of the pa-tients discontinued the study medication for any reason prematurely, with an equal proportion in the two groups.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Three interim efficacy analyses were performed after 45.7%, 76.1%, and 86.9% of the required events, with significance adjusted by the Lan-DeMets approximation of O'Brien-Fleming boundaries and a final two-sided P value for significance of 0.0394 or less.

    “In addition, three interim efficacy analyses were performed, after 45.7%, 76.1%, and 86.9% of the required events had occurred; adjustment of the level of significance to account for the three interim analyses was determined by the Lan-DeMets approximation of the O'Brien-Fleming boundaries for group sequential testing, with a final two-sided P value for significance of 0.0394 or less.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The false positive error rate for the three secondary end points was controlled with the Hochberg method.

    “The false positive error rate for the three secondary end points was controlled with the use of the Hochberg method.26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] source

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

    Study design and conductown data

    After a median of 6 years, 42% of patients in each group had discontinued the study medication without having died or without having had a primary end-point event.

    “After a median of 6 years, 42% of the patients in each group had discontinued the study medication without having died or without having had a primary end-point event.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The study was estimated to require 5250 events to give 90% power to detect a 9.375% lower relative risk for the primary end point with simvastatin-ezetimibe than with simvastatin monotherapy.

    “In the final protocol, we estimated that 5250 events would be required to give the study 90% power to detect a 9.375% lower relative risk for the primary end point with simvastatin-ezetimibe than with simvastatin monotherapy.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Intensive statin therapy, as compared with moderate-dose statin therapy, incrementally lowers LDL cholesterol levels and rates of nonfatal cardiovascular events.

    “Intensive statin therapy, as compared with moderate-dose statin therapy, incrementally lowers LDL cholesterol levels and rates of nonfatal cardiovascular events.[5][6][7][8][9]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5][6][7][8][9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All efficacy and safety analyses were performed in the intention-to-treat population.

    “All efficacy and safety analyses were performed in the intention-to-treat population.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    DCRI managed the database and performed the primary analyses independently using raw data, with TIMI and the sponsor verifying the analyses.

    “DCRI managed the database and performed the primary analyses independently using raw data; TIMI and the sponsor verified the analyses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The percentage of potential follow-up achieved was 91% for the primary end point and 97% for all-cause mortality.

    “The percentage of potential follow-up that was achieved -calculated as (number of patient-years of follow-up ÷ potential patient-years of follow-up) × 100was 91% for the primary end point and 97% for all-cause mortality.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Rules for stopping the study early at interim analyses were prespecified.

    “Rules for stopping the study early at interim analyses were prespecified.[22][23][24]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22][23][24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    A data and safety monitoring board oversaw the study.

    “A data and safety monitoring board oversaw the study.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Patients were randomly assigned in a 1:1 ratio and in a double-blind fashion to receive simvastatin plus ezetimibe or simvastatin plus placebo.

    “Patients received standard medical and interventional treatment for acute coronary syndrome 22 and were randomly assigned, in a 1:1 ratio and in a double-blind fashion, to receive, once daily, either simvastatin (at a dose of 40 mg) plus ezetimibe (at a dose of 10 mg) (simvastatinezetimibe group) or simvastatin (at a dose of 40 mg) plus placebo (simvastatin-monotherapy group).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Independent clinical-events committees, whose members were unaware of study-group assignments, adjudicated primary end-point events (excluding revascularization), cancer, and muscle-related events.

    “Independent clinical-events committees, whose members were unaware of the study-group assignments, adjudicated primary end-point events (excluding revascularization), cancer, and muscle-related events (details are provided in the Supplementary Appendix).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Adverse events were assessed in the intention-to-treat population.

    “Adverse events were assessed in the intention-to-treat population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The combination of simvastatin and ezetimibe resulted in a significantly lower risk of cardiovascular events than statin monotherapy, with a 2.0-percentage-point lower rate of the primary composite end point.

    “The combination of simvastatin and ezetimibe also resulted in a significantly lower risk of cardiovascular events than that with statin monotherapy, with a 2.0-percentage-point lower rate of the primary composite end point of”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All muscle and cancer events were adjudicated by a clinical events committee, whose members were unaware of the study-group assignments.

    “All muscle and cancer events were adjudicated by a clinical events committee, whose members were unaware of the study-group assignments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes.

    “When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IMPROVE-IT evaluated patients who had had an acute coronary syndrome, and the results are most relevant to that population.

    “First, we evaluated patients who had had an acute coronary syndrome, and our results are most relevant to that population.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The extent of benefit afforded by the simvastatin-ezetimibe combination is consistent with that seen in previous statin trials, with a similar reduction in cardiovascular events according to the degree of LDL cholesterol lowering.

    “The extent of benefit afforded by the simvastatin-ezetimibe combination is consistent with that seen in previous statin trials, with a similar reduction in cardiovascular events according to the degree of LDL cholesterol lowering (Fig. 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Scandinavian Simvastatin Survival Study Group, 1994, Lancet

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2] source
35 of 35

  • The paper relies on this without support.

    Whether additional clinical benefit would be observed with further reductions of LDL cholesterol to levels below 70 mg per deciliter has not been clear.

    “Whether additional clinical benefit would be observed with further reductions of LDL cholesterol to levels below 70 mg per deciliter has not been clear.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Compared with statin monotherapy, a combination of ezetimibe and statins reduces LDL-C by -24%, ApoB-100 by -14%, triglycerides by -12% and hsCRP by -13%, whilst maintaining HDL-C levels.

    “Compared with statin monotherapy, a combination of ezetimibe and statins reduces LDL-C by − 24%, ApoB-100 by − 14%, triglycerides by − 12% and high-sensitivity C-reactive protein (hsCRP) by − 13%, whilst maintaining HDL-C levels [59–61].”

    From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [59]

    The Lipid Data section reports 24% further LDL-C lowering with ezetimibe plus simvastatin and significantly lower apolipoprotein B, triglycerides, and hsCRP at one year. It does not give the claimed 14%, 12%, or 13% reductions for those three markers, or establish that HDL-C levels were maintained. The trial studied patients after acute coronary syndromes using simvastatin, rather than statins generally. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Risk is lower among patients who receive ezetimibe added to statin therapy than among patients who receive a statin alone.

    “and among patients who receive ezetimibe added to statin therapy than among those who receive a statin alone. 5”

    From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [5]

    The Efficacy End Points section reports a lower seven-year rate of the primary cardiovascular end point with simvastatin plus ezetimibe than with simvastatin alone. The claim omits that the trial studied patients after an acute coronary syndrome and that the reduction concerned cardiovascular events; the paper reports similar all-cause death rates in both groups. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Attenuation of statin treatment intensity probably also contributed to the rise in LDL cholesterol observed in the placebo group, in the on-treatment analysis in the alirocumab group, and in previous trials involving patients with acute coronary syndrome.

    “The last factor probably also contributed to the rise in LDL cholesterol observed in the placebo group, in the on-treatment analysis in the alirocumab group, and in previous trials involving patients who had an acute coronary syndrome. 5,21”

    From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [5]

    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

  • The rate of discontinuation of evolocumab injections because of adverse events ascribed to the drug compares favorably to rates with atorvastatin 80 mg daily (1.5% per year) and ezetimibe (1.1% per year) in other trials.

    “and compares favorably to the rates that have been found with atorvastatin at a dose of 80 mg daily (1.5% per year) and with ezetimibe (1.1% per year) in other trials.14,15”

    From Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (2017) · cites this paper as [15]

    The Safety section reports discontinuation owing to an adverse event in 10.6% of patients receiving simvastatin–ezetimibe, versus 10.1% receiving simvastatin alone. It does not report the cited 1.1% per-year rate or identify those adverse events as caused by ezetimibe. The atorvastatin comparison is not a finding of this trial. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • A delay between the onset of LDL cholesterol lowering and the emergence of the full clinical benefit has been well documented in trials of statins, ezetimibe, and other LDL cholesterol-lowering therapies.

    “A delay between the onset of LDL cholesterol lowering and the emergence of the full clinical benefit of the intervention in terms of clinical risk reduction has been well documented in trials of statins, ezetimibe, and other LDL cholesterollowering therapies.15,[21][22][23][24]”

    From Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (2017) · cites this paper as [15]

    The Efficacy End Points and Discussion sections report that the clinical benefit of adding ezetimibe to simvastatin appeared after about one year, while the Lipid Data section documents LDL lowering. This supports a delayed clinical benefit in this trial, but the paper does not establish that the same delay is well documented across trials of statins and other LDL-lowering therapies. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Scandinavian Simvastatin Survival Study Group, 1994, Lancet, 344, 1383
  2. GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico), 2000, Ital Heart J, 1, 810

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Related

Authors
Cannon, C. P., Blazing, M. A., Giugliano, R. P., McCagg, A., White, J. A., Theroux, P., Darius, H., Lewis, B. S., Ophuis, T. O., Jukema, J. W., De Ferrari, G. M., Ruzyllo, W., De Lucca, P., Im, K., Bohula, E. A., Reist, C., Wiviott, S. D., Tershakovec, A. M., Musliner, T. A., Braunwald, E., & Califf, R. M.
Affiliations
  • Brigham and Women's Hospital (US)
  • Canisius-Wilhelmina Ziekenhuis (NL)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2015-06-18
Volume
372
Issue
25
Pages
2387-2397
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1410489
OpenAlex
W1520609538
Semantic Scholar
33bafb0063a59a82a1f6e9a7d95c2b882edff0d3
Cited by
4,487
References
43
Citations by year
2026: 320 · 2025: 325 · 2024: 354 · 2023: 355 · 2022: 366 · 2021: 387 · 2020: 415 · 2019: 416 · 2018: 403 · 2017: 486 · 2016: 472 · 2015: 173 · 2014: 1 · 2013: 4 · 2012: 1
FWCI
514.71
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Intellectum (Universidad de La Sabana) (submittedVersion, other-oa)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • ORBi (University of Liège) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
  • Use Siena air (University of Siena) (submittedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Keywords
ezetimibe, simvastatin, statin therapy, acute coronary syndrome, LDL cholesterol lowering, cardiovascular events, lipid-lowering therapy, combination therapy, cardiovascular mortality, myocardial infarction, LDL cholesterol targets, cholesterol absorption inhibition, adverse drug reactions, cancer risk, gallbladder disease, hepatic adverse effects, coronary revascularization, stroke
MeSH terms
Ezetimibe, Aged, Anticholesteremic Agents, Azetidines, Cardiovascular Diseases, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Triglycerides, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Kaplan-Meier Estimate, Acute Coronary Syndrome

About these checks

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 2026-10-16.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-16.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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