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Cited by 459Lipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and LipoproteinsBlood Pressure and Hypertension Studies

2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk

Open access
Lloyd-Jones, Donald M., Morris, Pamela B., Ballantyne, Christie M., Birtcher, Kim K., Daly, David D., DePalma, Sondra M., Minissian, Margo B., Orringer, Carl E. +1 more·2016·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2016.03.519
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AI snapshot

Written from the paper’s full text.

TL;DR

This ACC Expert Consensus Decision Pathway provides practical guidance on when and how to add non-statin therapies to statin therapy for LDL-C lowering across the four 2013 ACC/AHA statin benefit groups, emphasizing shared decision making and net ASCVD risk-reduction benefit. It recommends ezetimibe as the first non-statin agent in many high-risk patients, reserves PCSK9 inhibitors for selected very-high-risk or familial hypercholesterolemia scenarios, and does not recommend niacin.

Key findings

  • The committee endorses the 2013 ACC/AHA four statin benefit groups and uses thresholds of ≥50% LDL-C reduction for high-intensity statin and 30% to <50% for moderate-intensity statin; if these are not achieved in adherent patients, clinicians should assess adherence, intensify statin therapy, and then consider non-statin therapy.
  • For stable clinical ASCVD without comorbidities, ezetimibe 10 mg daily is supported as the first non-statin agent; a bile acid sequestrant may be considered second-line if ezetimibe is not tolerated and triglycerides are <300 mg/dL; PCSK9 inhibitors are considered in selected very-high-risk patients, including those with ASCVD and baseline LDL-C ≥190 mg/dL or inadequate response after ezetimibe/BAS. Niacin is not recommended for routine use.
  • In diabetes without ASCVD, ezetimibe is preferred as the initial non-statin therapy; PCSK9 inhibitors do not have an established role for primary prevention in patients with diabetes in the absence of ASCVD or baseline LDL-C ≥190 mg/dL.
  • Cited evidence includes IMPROVE-IT, where adding ezetimibe to moderate-intensity statin produced a 6% relative / 2% absolute reduction in a composite ASCVD endpoint over 7 years; ezetimibe may lower LDL-C an additional 20–25% on average, and PCSK9 inhibitors may lower LDL-C an additional 60% on average. In Treating to New Targets, atorvastatin 80 mg vs 10 mg achieved mean LDL-C 77 vs 101 mg/dL and a 22% reduction in major cardiovascular events.

Methods

  • This is an ACC Expert Consensus Decision Pathway, not a formal systematic review, evidence grading, or evidence synthesis; it was informed by the September 16, 2015 “LDL: Address the Risk” Think Tank and subsequent writing-committee deliberation, with ACC support and no commercial support.
  • The committee endorsed the four statin benefit groups, considered higher-risk subgroups and comorbidities, and iteratively developed consensus algorithms for base cases and special populations; all pathways were finalized with full consensus.
  • The document is narrative and consensus-based, drawing on the 2013 ACC/AHA cholesterol guideline, selected RCTs such as IMPROVE-IT, TNT, SHARP, CORONA, and GISSI-HF, and prescribing information for non-statin agents.

Limitations

  • Stated: the process did not involve formal systematic reviews, grading of evidence, or synthesis of evidence; the pathway is intended to provide practical expert guidance rather than a single correct answer.
  • Stated: LDL-C thresholds are not firm triggers for adding medication but factors to consider; LDL-C measurement uncertainty exists, especially with Friedewald-calculated vs directly measured LDL-C at lower levels; RCT evidence gaps remain for combination therapy in stable ASCVD, primary prevention, heart failure, dialysis, and pregnancy, and PCSK9 inhibitor outcomes trials were ongoing.
  • Evident: many recommendations rely on expert opinion and extrapolation from limited or indirect trial data, and the document explicitly notes no data for non-statin therapies in heart failure and does not recommend PCSK9 inhibitors in heart failure or maintenance dialysis at that time.

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

Integrity signals

Registry

Crossref · 10.1016/j.jacc.2016.03.519

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 112 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The only trial of high-intensity statin therapy in primary prevention was performed in a population without diabetes.

    “The only trial of high-intensity statin therapy in primary prevention was performed in a population without diabetes (29)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Ridker, 2008, Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein, N Engl J Med source

      Not checked in the free run.

  • Premisecitation

    This risk is accelerated in the presence of other ASCVD risk factors.

    “This risk is accelerated in the presence of other ASCVD risk factors (22,23).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Goldberg, 2011, Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia, J Clin Lipidol source

      Not checked in the free run.

    • cites [23] Wiegman, 2015, Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment, Eur Heart J source

      Not checked in the free run.

  • Premisecitation

    Statins have demonstrated net benefit for the 4 statin benefit groups.

    “Statins clearly have demonstrated net benefit for the 4 statin benefit groups, whereas other drug therapies available in 2013 had either marginal net ASCVD risk-reduction benefit or had been shown not to provide additional benefit beyond statins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • Premisereasoning

    The 2013 ACC/AHA cholesterol guideline panel did not make specific recommendations regarding lipoprotein goals of therapy.

    “Because no large RCTs have evaluated the outcome of drug titration to specific LDL-C targets, the 2013 ACC/AHA cholesterol guideline panel did not make specific recommendations regarding lipoprotein goals of therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • Premisecitation

    There can be significant discrepancies between directly measured and calculated LDL-C levels within the same sample, especially at lower LDL-C levels.

    “Nonetheless, the committee acknowledges that there can be significant discrepancies in levels of directly measured versus calculated LDL-C within the same sample, especially at lower LDL-C levels (19,20).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Martin, 2013, Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [20] Mora, 2009, Comparison of LDL cholesterol concentrations by Friedewald calculation and direct measurement in relation to cardiovascular events in 27331 women, Clin Chem source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 30
  • May combine two claims. 32
  • The quote only partly states this claim. 3

  • Classified as probably not a substantial claim.

    Premisecitation

    Lifestyle modification (heart-healthy diet, regular exercise, tobacco avoidance, healthy weight) remains a critical component of ASCVD risk reduction, both before and in concert with cholesterol-lowering drug therapies.

    “In agreement with the 2013 ACC/AHA cholesterol guideline, for all patient groups, the current consensus emphasizes that lifestyle modification (i.e., adherence to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remains a critical component of ASCVD risk reduction, both before and in concert with the use of cholesterol-lowering drug”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 2013 ACC/AHA cholesterol guideline

      Not checked in the free run.

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

    Study design and conductnone given

    A public comment period was held to obtain further feedback.

    “A public comment period was also held to obtain further feedback.”
    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 conductnone given

    A formal peer review process was completed consistent with ACC policy and included expert reviewers nominated by the ACC.

    “A formal peer review process was completed consistent with ACC policy and included expert reviewers nominated by the ACC (see Appendix 2).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The 2013 ACC/AHA guideline panel indicated that in those already on a statin, in whom baseline LDL-C is unknown, an LDL-C level <100 mg/dL was observed in most individuals receiving high-intensity statin therapy.

    “For example, the guideline panel indicated that”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The expert consensus writing committee began its deliberations by endorsing the construct of the 4 statin benefit groups identified by the 2013 ACC/AHA cholesterol guideline.

    “The expert consensus writing committee began its deliberations by endorsing the construct of the 4 statin benefit groups identified by the 2013 ACC/AHA cholesterol guideline (Table 1) (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

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

    Premisecitation

    The 2013 ACC/AHA cholesterol guideline panel determined that a high level of RCT evidence supports the use of an initial fasting lipid panel followed by a second fasting lipid panel 4 to 12 weeks after initiation of statin therapy, to determine a patient's adherence and confirm anticipated response to therapy.

    “The panel determined that a high level of RCT evidence supports the use of an initial fasting lipid panel (total cholesterol [TC], triglycerides, high-density lipoprotein cholesterol [HDL-C], and calculated LDL-C) followed by a second fasting lipid panel 4 to 12 weeks after initiation of statin therapy, to determine a patient's adherence and confirm anticipated response to therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The ACC recognized that clinicians and patients may seek firmer and more specific guidance on the adequacy of statin therapy and whether or when to use non-statin therapies if response to statins is deemed inadequate.

    “The ACC recognized that clinicians and patients may seek firmer and more specific guidance on the adequacy of statin therapy and whether or when to use non-statin therapies if response to statins is deemed inadequate.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Assuming adherence to therapy, patients with LDL-C levels above the range achieved in the RCTs may not achieve maximal benefit and might be considered for additional therapy.

    “Therefore, assuming adherence to therapy, patients with LDL-C levels above that range may not achieve maximal benefit and might be considered for additional therapy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Patients in the RCTs demonstrating efficacy and safety of LDL-C lowering therapy tended to achieve absolute LDL-C levels within a given range.

  • Classified as probably not a substantial claim.

    Premisecitation

    The 2013 ACC/AHA cholesterol guideline's evidence-based findings regarding appropriate intensity statin therapy and indicators of efficacy (e.g., ≥50% LDL-C reduction for high-intensity statin doses and 30% to <50% reduction for moderate-intensity doses) are endorsed.

    “The expert consensus writing committee endorsed the evidence-based findings from the 2013 ACC/AHA cholesterol guideline regarding the use of appropriate intensity statin therapy and the indicators of efficacy (e.g., $50% LDL-C reduction for high-intensity statin doses and 30% to <50% reduction for moderateintensity doses).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 2013 ACC/AHA cholesterol guideline

      Not checked in the free run.

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

    Study design and conductnone given

    This process did not involve formal systematic reviews, grading of evidence, or synthesis of evidence.

    “It should be noted that this process did not involve formal systematic reviews, grading of evidence, or synthesis of evidence.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Participants in the LDL: Address the Risk Think Tank identified the need for expert consensus guidance regarding the incorporation of non-statin therapies into treatment strategies for higher-risk patients as a critical gap in clinical care.

    “Participants in this LDL: Address the Risk Think Tank identified the need for expert consensus guidance regarding the incorporation of non-statin therapies into treatment strategies for higherrisk patients as a critical gap in clinical care.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All members of the writing committee, as well as those selected to serve as peer reviewers, were required to disclose relationships with industry and other entities (RWI).

    “All members of the writing committee, as well as those selected to serve as peer reviewers of this document, were required to disclose relationships with industry and other entities (RWI).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The work of the writing committee was supported exclusively by the ACC without commercial support.

    “The work of the writing committee was supported exclusively by the ACC without commercial support.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the Treating to New Targets trial, patients receiving 80 mg of atorvastatin achieved a mean LDL-C of 77 mg/dL, with the majority achieving <100 mg/dL.

    “The patients receiving 80 mg of atorvastatin achieved a mean LDL-C of 77 mg/dL, with the majority achieving <100 mg/dL, whereas the patients receiving 10 mg of atorvastatin achieved a mean LDL-C of 101 mg/dL.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] LaRosa, 2005, Intensive lipid lowering with atorvastatin in patients with stable coronary disease, N Engl J Med source

      Not checked in the free run.

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

    Study design and conductnone given

    All issues were discussed and all pathways were finalized with full consensus of the committee members.

    “All issues were discussed and all pathways were finalized with full consensus of the committee members.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In patients with ACS, ezetimibe-simvastatin combination therapy improves ASCVD outcomes and has demonstrated safety compared with simvastatin monotherapy.

    “given the benefits on ASCVD outcomes and demonstrated safety of ezetimibe in patients with ACS treated with ezetimibe-simvastatin versus simvastatin monotherapy (Table 3) (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The combination of ezetimibe with moderate-intensity simvastatin versus simvastatin monotherapy has improved ASCVD outcomes and demonstrated safety.

    “the addition of ezetimibe may be considered given the improved ASCVD outcomes and demonstrated safety of the combination of ezetimibe with moderate-intensity simvastatin versus simvastatin monotherapy (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PCSK9 inhibitors alirocumab and evolocumab dramatically reduce LDL-C levels over and above statin therapy, with favorable short-term outcomes data up to 18 months.

    “(10,11).These agents dramatically reduce LDL-C levels over and above statin therapy, with favorable short-term outcomes data up to 18 months (11,12).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Sabatine, 2015, Efficacy and safety of evolocumab in reducing lipids and cardiovascular events, N Engl J Med source

      Not checked in the free run.

    • cites [12] Eckel, 2014, 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    Patients with ASCVD and primary severe elevations of LDL-C ≥190 mg/dL have very high risk for future ASCVD events because of lifetime exposure to markedly elevated LDL-C levels.

    “Patients with ASCVD and primary, severe elevations of LDL-C $190 mg/dL have very high risk for future ASCVD events because of their lifetime exposure to markedly elevated LDL-C levels.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The 2013 ACC/AHA cholesterol guideline panel recommended using either high- or moderate-intensity statin therapy for patients in the 4 statin benefit groups at risk for ASCVD in primary and secondary prevention scenarios, with dose adjustments as necessitated by factors such as adverse effects, advanced age, drug-drug interactions, and comorbidities.

    “Instead, the panel recommended initiating either high-or moderate-intensity statin therapy on the basis of patient ASCVD risk characteristics and the potential for net benefit; however, the panel did note that groups of patients with the greatest benefit from statin therapy tended to fall into ranges of LDL-C indicating efficacy of statin therapy.”
    • Also stated in: § TABLE OF CONTENTS · plain
      “In summary, the 2013 ACC/AHA cholesterol guideline panel recommended using either high-or moderateintensity statin therapy for patients in the 4 statin benefit groups at risk for ASCVD in primary and secondary prevention scenarios, with dose adjustments as necessitated by factors such as adverse effects, advanced age, drug-drug interactions, and comorbidities.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The 2013 ACC/AHA guideline panel approach was centrally based on the concept of net ASCVD risk-reduction benefit, defined as the likelihood of preventing a major ASCVD event or death being greater than the likelihood of a serious adverse event with a given drug therapy.

    “Central to the 2013 ACC/AHA guideline panel approach was the concept of”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients treated with statin versus placebo, or with higher- versus lower-intensity statin therapy, experienced significantly greater ASCVD risk reduction with minimal serious adverse event rates, typically similar to the adverse event rates in placebo comparator groups.

    “Patients treated with statin versus placebo, or with higher-versus lower-intensity statin therapy, experienced significantly greater ASCVD risk reduction with minimal serious adverse event rates, typically similar to the adverse event rates in placebo comparator groups (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Baigent, 2010, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other drug therapies available in 2013 had either marginal net ASCVD risk-reduction benefit or had been shown not to provide additional benefit beyond statins.

    “Statins clearly have demonstrated net benefit for the 4 statin benefit groups, whereas other drug therapies available in 2013 had either marginal net ASCVD risk-reduction benefit or had been shown not to provide additional benefit beyond statins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    There are no clear indications for the routine use of niacin preparations as additional non-statin therapies.

    “On the basis of currently available evidence of non-efficacy and potential harms, the committee judged that there are no clear indications for the routine use of niacin preparations as additional non-statin therapies, and niacin is therefore not recommended for use in any of the clinical situations addressed below.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Niacin preparations have non-efficacy and potential harms as additional non-statin therapies.

  • May combine two claims.

    Premisecitation

    The combination of ezetimibe with moderate-intensity simvastatin improves ASCVD outcomes and has demonstrated safety compared with simvastatin monotherapy.

    “the addition of ezetimibe may be considered based upon the improved ASCVD outcomes and demonstrated safety of the combination of ezetimibe with moderate-intensity simvastatin versus simvastatin monotherapy (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted). The quote only partly states this claim.

    Premisecitation

    Lomitapide increases hepatic fat (hepatic steatosis) with or without concomitant increases in transaminases.

    “Increases hepatic fat (hepatic steatosis) with or without concomitant increases in transaminases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites PI

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ezetimibe inhibits Niemann-Pick C1 like 1 (NPC1L1) protein and reduces cholesterol absorption in the small intestine.

    “Mechanism of action: Inhibits Niemann-Pick C1 like 1 (NPC1L1) protein; reduces cholesterol absorption in small intestine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Merck and Co., Inc. Zetia Prescribing Information. Revised August 2013. Available at: www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf. Accessed February 27, 2016.

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Patients without clinical ASCVD or diabetes, who have LDL-C 70 to 189 mg/dL and an estimated 10-year risk for ASCVD of >=7.5%, were found to be in a group with net benefit from statin therapy by the 2013 ACC/AHA cholesterol guideline panel.

    “Patients without clinical ASCVD or diabetes, who have LDL-C 70 to 189 mg/dL and an estimated 10-year risk for ASCVD of $7.5%, were found to be in a group with net benefit from statin therapy by the 2013 ACC/AHA cholesterol guideline panel (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Evolocumab, when added to maximally tolerated statin therapy, reduces LDL-C by an additional 64% at 140 mg every 2 weeks and 58% at 420 mg SQ every 4 weeks.

    “When added to maximally tolerated statin therapy evolocumab 140 mg every 2 weeks and 420 mg SQ every 4 weeks, Y LDL-C by an additional 64% and 58%, respectively.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Sanofi Aventis, US, LLC. Praluent Prescribing Information. Revised October 2015. Available at: http://products.sanofi.us/praluent/praluent.pdf. Accessed February 27, 2016.

      Not checked in the free run.

    • cites [38] Amgen Inc. Repatha Prescribing Information. Revised August 2015. Available at: http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf. Accessed February 27, 2016.

      Not checked in the free run.

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

    Premisenone given

    Daily dose of low-intensity statin lowers LDL-C, on average, by <30%.

    “Daily dose lowers LDL-C, on average, by <30%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In SHARP, simvastatin plus ezetimibe reduced LDL-C and reduced the primary endpoint of first major ASCVD event [nonfatal MI or CHD death, non-hemorrhagic stroke, or any arterial revascularization procedure] compared to placebo over a median follow-up of 4.9 years.

    “SHARP (33) (Simvastatin plus ezetimibe reduced LDL-C and reduced primary endpoint of first major ASCVD event [nonfatal MI or CHD death, non-hemorrhagic stroke, or any arterial revascularization procedure] compared to placebo over a median f/u of 4.9 years).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Baigent, 2011, 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Treating to New Targets trial, patients with CHD who received 10 mg atorvastatin daily had a 5-year event rate of 10.9%, and those who received 80 mg atorvastatin daily had a 5-year event rate of 8.7%.

    “in the Treating to New Targets trial, patients with CHD who received 10 mg of atorvastatin daily had a 5-year event rate of 10.9%, and those who received 80 mg of atorvastatin daily had a 5-year event rate of 8.7%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Treating to New Targets trial

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PCSK9 inhibitors are human monoclonal antibodies to PCSK9 that bind to PCSK9 and increase the number of LDL receptors available to clear circulating LDL.

    “Mechanism of action: Human monoclonal antibody to PCSK9.Binds to PCSK9 and increases the number of LDL receptors available to clear circulating LDL.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Sanofi Aventis, US, LLC. Praluent Prescribing Information. Revised October 2015. Available at: http://products.sanofi.us/praluent/praluent.pdf. Accessed February 27, 2016.

      Not checked in the free run.

    • cites [38] Amgen Inc. Repatha Prescribing Information. Revised August 2015. Available at: http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf. Accessed February 27, 2016.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In IMPROVE-IT, the addition of ezetimibe to moderate-intensity statin in patients with recent ACS resulted in incremental lowering of LDL-C and reduced the primary composite endpoint of CV death, nonfatal MI, UA requiring re-hospitalization, coronary revascularization [>=30 days after randomization], or nonfatal stroke.

    “IMPROVE-IT (8) (The addition of ezetimibe to moderate-intensity statin in patients with recent ACS resulted in incremental lowering of LDL-C and reduced primary composite endpoint of CV death, nonfatal MI, UA requiring re-hospitalization, coronary revascularization [$30 days after randomization], or nonfatal stroke.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The net ASCVD risk-reduction benefit is likely to be lower in primary prevention without diabetes.

    “Because the net ASCVD risk-reduction benefit is likely to be lower in primary prevention without diabetes, few patients should be considered for additional therapies at this time beyond a maximally tolerated intensity of statin.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Premisecitation

    In patients with HoFH, adding lomitapide to baseline lipid-lowering therapy reduces LDL-C by a mean of 40% and median of 50% (per prescribing information).

    “Mean and median percent changes in LDL-C from baseline when added to baseline lipidlowering therapy were -40% and -50%, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites PI

      Not checked in the free run.

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

    Premisereasoning

    Strong and moderate CYP3A4 inhibitors are contraindicated with lomitapide.

    “Strong and moderate CYP3A4 inhibitors are contraindicated with lomitapide.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites PI

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisenone given

    The long-term consequences of hepatic steatosis from mipomersen and lomitapide are unknown.

    “long-term consequences of hepatic steatosis unknown”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Higher-risk subgroups of patients with diabetes are potential candidates for high-intensity statin therapy.

    “Higher-risk subgroups of patients with diabetes are potential candidates for highintensity statin therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Niacin preparations have been associated with no benefit and potential for significant harms when added to statin therapy.

    “Niacin preparations have been associated with no benefit and potential for significant harms when added to statin therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites niacin

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neither the CORONA nor the GISSI-HF trial demonstrated significant reductions in primary endpoints or major secondary endpoints.

    “Neither the CORONA nor the GISSI-HF trial demonstrated significant reductions in primary endpoints or major secondary endpoints.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites CORONA

      Not checked in the free run.

    • cites GISSI-HF

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with LDL-C ≥190 mg/dL are more likely to have HeFH or HoFH, genetic disorders associated with severe hypercholesterolemia, and a family history of severe hypercholesterolemia and premature ASCVD.

    “Patients with LDL $190 mg/dL are more likely to have HeFH or HoFH, genetic disorders associated with severe hypercholesterolemia, and a family history of severe hypercholesterolemia and premature ASCVD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Goldberg, 2011, Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia, J Clin Lipidol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although all patients with baseline LDL-C ≥190 mg/dL are at high risk for first and recurrent ASCVD events because of lifetime exposure, the presence of concomitant risk factors or risk markers for ASCVD further increases ASCVD risk significantly.

    “Although all patients with baseline LDL-C $190 mg/dL are at high risk for first and recurrent ASCVD events because of their lifetime exposure, the presence of concomitant risk factors or risk markers for ASCVD (including a family history of premature ASCVD events, tobacco use, diabetes, hypertension, CKD, evidence of subclinical atherosclerosis, elevated lipoprotein(a), or elevated high-sens”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Combination therapy with ezetimibe plus moderate-intensity statin demonstrated a statistically significant but clinically modest reduction in events over 7 years, with no safety concerns observed with ezetimibe addition.

    “Combination therapy demonstrated a statistically significant, but clinically modest, reduction in events over 7 years of follow-up, and no safety concerns were observed with the addition of ezetimibe (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the SHARP trial, the reduction in major atherosclerotic events was smaller and non-significant in dialysis patients, particularly hemodialysis patients, although power was limited to detect benefit in this smaller subgroup.

    “the reduction was smaller and non-significant in dialysis patients, and particularly hemodialysis patients (although power was limited to detect benefit in this smaller subgroup).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Baigent, 2011, 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 source

      Not checked in the free run.

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

    Premisecitation

    Familial hypercholesterolemia has an autosomal codominant pattern of inheritance and is caused most commonly by mutations in the gene coding for the LDL receptor, with >1,600 different identified mutations.

    “This disorder has an autosomal codominant pattern of inheritance and is caused most commonly by mutations in the gene coding for the LDL receptor, with >1,600 different identified mutations(22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Goldberg, 2011, Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia, J Clin Lipidol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The effects of acute ASCVD events appear to be more severe among patients with diabetes.

    “the effects of acute ASCVD events appear to be more severe among patients with diabetes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The FDA approved two monoclonal antibodies to PCSK9, alirocumab and evolocumab, which inhibit binding of PCSK9 to the LDL receptor, thus increasing LDL receptor density.

    “the FDA approved 2 monoclonal antibodies to PCSK9, alirocumab and evolocumab, which inhibit binding of PCSK9 to the LDL receptor, thus increasing LDL receptor density.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites FDA

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    A larger amount of data support the use of moderate-intensity statin therapy for secondary prevention in individuals with clinical ASCVD who are >75 years of age; however, the limited information available does not clearly support initiation of high-intensity statin therapy for secondary prevention in individuals >75 years of age.

    “A larger amount of data support the use of moderate-intensity statin therapy for secondary prevention in individuals with clinical ASCVD who are >75 years of age; however, the limited information available does not clearly support initiation of highintensity statin therapy for secondary prevention in individuals >75 years of age.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The committee identified higher-risk subgroups of patients with diabetes for special consideration, including those with concomitant ASCVD risk factors, predicted 10-year ASCVD risk ≥7.5%, CKD, albuminuria, retinopathy, evidence of subclinical atherosclerosis, elevated lipoprotein(a), or elevated high-sensitivity C-reactive protein.

    “The committee identified higher-risk subgroups of patients with diabetes for special consideration, including those with concomitant ASCVD risk factors, predicted 10-year ASCVD risk $7.5% by the Pooled Cohort Equations, CKD, albuminuria, retinopathy, evidence of subclinical atherosclerosis, elevated lipoprotein(a), or elevated high-sensitivity C-reactive protein.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Patients with diabetes are at higher risk for ASCVD events due to diabetes itself and to the concomitant burden of other cardiometabolic risk factors that tend to cluster in patients with type 1 or type 2 diabetes.

    “Patients with diabetes are at higher risk for ASCVD events due to diabetes itself and also to the concomitant burden of other cardiometabolic risk factors that tend to cluster in patients with type 1 or type 2 diabetes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HPS2-THRIVE showed no benefit and significant harms from a long-acting niacin/laropiprant preparation added to moderate-intensity simvastatin compared with simvastatin alone in patients with clinical ASCVD, despite further LDL-C lowering with niacin.

    “the results of HPS2-THRIVE (published in 2014) (9) subsequently showed no benefit and significant harms from a long-acting niacin/laropiprant preparation in addition to moderate-intensity statin (simvastatin) compared with moderate-intensity statin alone in patients with clinical ASCVD, despite further lowering of LDL-C with niacin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites HPS2-THRIVE

      Not checked in the free run.

    • cites [9] Landray, 2014, Effects of extended-release niacin with laropiprant in high-risk patients, N Engl J Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The expert consensus writing committee endorses the evidence-based approaches to ASCVD risk reduction in adults enumerated in the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol.

    “The expert consensus writing committee endorses the evidence-based approaches to ASCVD risk reduction in adults enumerated in the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Long-term drug therapy of patients with severe hypercholesterolemia can substantially reduce the risk of ASCVD and requires lifelong treatment and regular follow-up.

    “Long-term drug therapy of patients with severe hypercholesterolemia can substantially reduce the risk of ASCVD and requires lifelong treatment and regular follow-up.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Both CORONA and GISSI-HF were notable for very high all-cause mortality rates experienced by study participants regardless of randomization status, suggesting very high competing risks.

    “Both trials were notable for the very high all-cause mortality rates experienced by study participants regardless of randomization status, suggesting very high competing risks”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites CORONA

      Not checked in the free run.

    • cites GISSI-HF

      Not checked in the free run.

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

    Premisecitation

    As per the ACC/AHA guideline, fewer people >75 years of age were enrolled in the statin RCTs, but available evidence does support the continuation of statins beyond 75 years of age in persons who are already taking and tolerating these drugs.

    “As per the ACC/AHA guideline, fewer people >75 years of age were enrolled in the statin RCTs, but available evidence does support the continuation of statins beyond 75 years of age in persons who are already taking and tolerating these drugs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites ACC/AHA guideline

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Colesevelam post-marketing reports include seizure activity or decreased phenytoin levels in patients receiving phenytoin, decreased INR in patients receiving warfarin, increased TSH in patients receiving thyroid hormone replacement therapy, bowel obstruction, dysphagia, esophageal obstruction, fecal impaction, hypertriglyceridemia, pancreatitis, and increased transaminases.

    “Post-marketing reports with colesevelam include [ seizure activity or Y phenytoin levels in patients receiving phenytoin, Y INR in patients receiving warfarin, [ TSH in patients receiving thyroid hormone replacement therapy, bowel obstruction, dysphagia, esophageal obstruction, fecal impaction, hypertriglyceridemia, pancreatitis, and increased transaminases”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites PI

      Not checked in the free run.

57 of 57

  • The paper relies on this without support.

    Lowering LDL-C with non-statin therapies reduces ASCVD risk.

    “These agents dramatically reduce LDL-C levels over and above statin therapy, with favorable short-term outcomes data up to 18 months (11,12).Longterm cardiovascular outcomes trials are ongoing for both alirocumab and evolocumab, as well as for bococizumab, a PCSK9 inhibitor that is not yet FDA approved.”

  • The paper relies on this without support.

    There is a critical gap in clinical care regarding the incorporation of non-statin therapies into treatment strategies for higher-risk patients.

    “Participants in this LDL: Address the Risk Think Tank identified the need for expert consensus guidance regarding the incorporation of non-statin therapies into treatment strategies for higherrisk patients as a critical gap in clinical care.”

  • The paper relies on this without support.

    Adherence to both medication and lifestyle regimens is required for ASCVD risk reduction.

    “Adherence to both medication and lifestyle regimens is required for ASCVD risk reduction.”

  • The paper relies on this without support.

    The overwhelming body of evidence for ASCVD risk reduction with lipid-lowering therapies is from statin RCTs.

    “Because the overwhelming body of evidence for ASCVD risk reduction with lipid-lowering therapies is from statin RCTs, evidencebased statin therapy of appropriate intensity is recommended in all 4 statin benefit groups”

  • The paper relies on this without support.

    A careful history can help to determine whether symptoms are consistent with statin-related effects, which tend to be myalgias or weakness in large proximal muscle groups.

    “A careful history can help to determine whether symptoms are consistent with statin-related effects, which tend to be myalgias or weakness in large proximal muscle groups.”

  • The paper relies on this without support.

    Some patients, such as women, individuals of Asian descent, and the elderly, may be at increased risk for statin-related muscle symptoms.

    “Some patients, such as women, individuals of Asian descent, and the elderly, may be at increased risk for statin-related muscle symptoms; however, these patients may be able to tolerate a lower statin intensity, an alternative statin, or alternative dosing strategies without problems.”

  • The paper relies on this without support.

    These patients may be able to tolerate a lower statin intensity, an alternative statin, or alternative dosing strategies without problems.

    “however, these patients may be able to tolerate a lower statin intensity, an alternative statin, or alternative dosing strategies without problems.”

  • The paper relies on this without support.

    Patients in the RCTs demonstrating efficacy and safety of LDL-C lowering therapy tended to achieve absolute LDL-C levels within a given range.

    “In addition, the committee acknowledged that patients in the RCTs demonstrating efficacy and safety of LDL-C lowering therapy tended to achieve absolute LDL-C levels within a given range.”

  • The authors state this as an assumption.

    These algorithms assume that the patient is currently taking or has attempted to take a statin, as a result of shared decision making, and that the clinician and patient are trying to determine whether additional therapy is needed to reduce ASCVD risk further.

    “These algorithms assume that the patient is currently taking or has attempted to take a statin, as a result of shared decision making, and that the clinician and patient are trying to determine whether additional therapy is needed to reduce ASCVD risk further.”

  • The authors state this as an assumption.

    These algorithms were crafted based on the principle of potential net ASCVD risk-reduction benefit, meaning that the potential benefits of additional non-statin therapy should outweigh any potential for harm.

    “These algorithms were crafted based on the principle of potential net ASCVD risk-reduction benefit, meaning that the potential benefits of additional non-statin therapy should outweigh any potential for harm.”

  • The paper relies on this without support.

    There is not a universally accepted definition of statin intolerance.

    “Whereas there is not a universally accepted definition of statin intolerance, most experts recommend that patients are documented to have unacceptable muscle-related symptoms that resolve with discontinuation of therapy and occur with rechallenge on at least 2 to 3 statins, preferably ones that use different metabolic pathways and have different lipophilicity, and 1 of which is prescribed at the”

  • The paper relies on this without support.

    Niacin preparations have non-efficacy and potential harms as additional non-statin therapies.

    “On the basis of currently available evidence of non-efficacy and potential harms, the committee judged that there are no clear indications for the routine use of niacin preparations as additional non-statin therapies”

  • The paper relies on this without support.

    The majority of RCTs used the Friedewald equation.

    “given that the majority of RCTs used this method”

  • The paper relies on this without support.

    The Friedewald equation is the most widely available means in clinical practice.

    “that it is the most widely available means in clinical practice”

  • The paper relies on this without support.

    The Friedewald equation tends to cost less.

    “and that it tends to cost less”

  • The paper relies on this without support.

    There is a gap in RCT evidence demonstrating outcomes benefits of using combination therapy in stable clinical ASCVD patients.

    “Although there is a gap in RCT evidence demonstrating outcomes benefits of using combination therapy in stable clinical ASCVD patients”

  • The paper relies on this without support.

    There is a gap in the evidence demonstrating outcomes benefit when combined with high-intensity statin therapy.

    “Although there is a gap in the evidence demonstrating outcomes benefit when combined with high-intensity statin therapy”

  • The paper relies on this without support.

    Patients with LDL-C ≥190 mg/dL are more likely to have heterozygous or homozygous familial hypercholesterolemia, genetic disorders associated with severe hypercholesterolemia, and a family history of severe hypercholesterolemia and premature ASCVD.

    “Patients with LDL-C $190 mg/dL are more likely to have heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, genetic disorders associated with severe hypercholesterolemia, and a family history of severe hypercholesterolemia and premature ASCVD.”

  • The paper relies on this without support.

    Early treatment is highly beneficial.

    “Early treatment is highly beneficial.”

  • The paper relies on this without support.

    Long-term drug therapy of patients with severe hypercholesterolemia can substantially reduce the risk of ASCVD.

    “Long-term drug therapy of patients with severe hypercholesterolemia can substantially reduce the risk of ASCVD”

  • The paper relies on this without support.

    Hypercholesterolemia in these high-risk individuals is often genetically determined.

    “Because hypercholesterolemia in these high-risk individuals is often genetically determined”

  • The paper relies on this without support.

    PCSK9 inhibitors have greater LDL-C lowering efficacy than ezetimibe or BAS.

    “given PCSK9 inhibitors' greater LDL-C lowering efficacy”

  • The paper relies on this without support.

    Elevated non-HDL-C is frequent despite near-normal levels of LDL-C in patients with diabetes.

    “Due to the frequency of elevated non-HDL-C despite near-normal levels of LDL-C in patients with diabetes”

  • The paper relies on this without support.

    Patients with ASCVD and comorbidities are at higher risk.

    “given the higher-risk nature of this patient population with comorbidities”

  • The paper relies on this without support.

    Hypercholesterolemia in high-risk individuals with LDL-C >=190 mg/dL is often genetically determined.

    “Because hypercholesterolemia in these high-risk individuals is often genetically determined”

  • The paper relies on this without support.

    Patients with LDL-C >=190 mg/dL may have variable responses to pharmacological therapies depending on gene mutation, expression, and pattern of inheritance.

    “Depending on the gene mutation, expression, and pattern of inheritance (i.e., homozygous or heterozygous), patients with LDL-C $190 mg/dL may have variable responses to pharmacological therapies.”

  • The paper relies on this without support.

    Elevated non-HDL-C is frequent despite near-normal levels of LDL-C in diabetics.

    “Due to the frequency of elevated non-HDL-C despite near-normal levels of LDL-C in diabetics”

  • The paper relies on this without support.

    Bile acid sequestrants may have a modest hypoglycemic effect that may benefit some diabetic patients if fasting triglycerides are <300 mg/dL.

    “BAS may have a modest hypoglycemic effect that may be of benefit in some diabetic patients if fasting triglycerides are <300 mg/dL.”

  • The paper relies on this without support.

    Colesevelam has a modest hypoglycemic effect that may benefit some diabetic patients with fasting triglycerides <300 mg/dL or in patients who are ezetimibe intolerant.

    “Colesevelam has a modest hypoglycemic effect that may be of benefit in some diabetic patients with fasting triglycerides <300 mg/dL or in patients who are ezetimibe intolerant.”

  • The paper relies on this without support.

    Younger patients without ASCVD but with ASCVD risk factors typically have low 10-year predicted risks for ASCVD but high lifetime predicted risks.

    “Younger patients without ASCVD but with ASCVD risk factors typically have low 10-year predicted risks for ASCVD but high lifetime predicted risks.”

  • The paper relies on this without support.

    Making decisions for drug therapy based on lifetime ASCVD risk is problematic because of limited data on treatment of younger adults and on long-term safety and efficacy of lipid-lowering therapy.

    “However, making decisions for drug therapy based on lifetime ASCVD risk is problematic because of the limited data on treatment of younger adults and on long-term safety and efficacy of lipid-lowering therapy.”

  • The paper relies on this without support.

    Patients with CKD not on dialysis but without ASCVD, on statins for primary prevention, are at higher risk than the general population.

    “Similarly, patients with CKD not on dialysis but without ASCVD, on statins for primary prevention, are considered to be at higher risk than the general population (Figures 4 and 5).”

  • The paper relies on this without support.

    There is a gap in the evidence demonstrating outcomes benefit when ezetimibe is combined with high-intensity statin therapy.

    “Although there is a gap in the evidence demonstrating outcomes benefit when combined with high-intensity statin therapy”

  • The authors state this as an assumption.

    The algorithms assume the patient is in one of the four evidence-based statin benefit groups identified in the 2013 ACC/AHA cholesterol guideline.

    “These algorithms begin with the assumption that the patient is in 1 of the 4 evidence-based statin benefit groups identified in the 2013 ACC/AHA cholesterol guideline:”

  • The authors state this as an assumption.

    Reductions in CVD events with LDL apheresis are proportional to the degree of LDL cholesterol lowering.

    “but it is reasonable to assume reductions in CVD events are proportional to the degree of LDL cholesterol lowering.”

  • The paper relies on this without support.

    For each 40 mg/dL reduction in LDL-C using safe and evidence-based therapies, there is an approximate 20% relative risk reduction in ASCVD.

    “For each 40 mg/ dL reduction in LDL-C using safe and evidence-based therapies, there appears to be an approximate 20% relative risk reduction in ASCVD.”

  • The paper relies on this without support.

    With weekly or biweekly LDL apheresis, average LDL-C can decrease to approximately 50-60% of original levels.

    “With weekly or biweekly treatment, average LDL-C can Y to w50-60% of the original levels.”

  • The paper relies on this without support.

    LDL-C increases after each apheresis session but does not return to the original level.

    “LDL-C increases after each apheresis session but does not return to the original level.”

  • The paper relies on this without support.

    With intake of 3.0-12.4 g/day, soluble/viscous fiber reduces mean TC and LDL-C relative to control by 9.7 and 11.6 mg/dL, respectively.

    “With intake of 3.0-12.4g/day, mean TC and LDL-C levels were Yrelative to control by 9.7 and 11.6 mg/dL, respectively.”

  • The paper relies on this without support.

    Soluble/viscous fiber has few safety concerns.

    “Few safety concerns.”

  • The paper relies on this without support.

    No data exist examining the use of non-statin therapies in heart failure patients, and heart failure is an exclusion criterion in recent PCSK9 inhibitor trials.

    “No data exist examining the use of non-statin therapies in heart failure patients, and heart failure is an exclusion criterion in recent PCSK9 inhibitor trials.”

  • The paper relies on this without support.

    The approval of 2 PCSK9 inhibitors for LDL-C lowering in specific high-risk patients has resulted in gaps in expert guidance regarding the role of available non-statin therapies.

    “In addition, the approval of 2 PCSK9 inhibitors for LDL-C lowering in specific high-risk patients has resulted in gaps in expert guidance regarding the role of available non-statin therapies.”

  • The paper relies on this without support.

    Statin is the most effective initial therapy.

    “given that this is the most effective initial therapy.”

  • The authors state this as an assumption.

    The patient is currently taking or has attempted to take a statin.

    “assume that the patient is currently taking or has attempted to take a statin”
44 of 44

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Authors
Lloyd-Jones, D. M., Morris, P. B., Ballantyne, C. M., Birtcher, K. K., Daly, D. D., DePalma, S. M., Minissian, M. B., Orringer, C. E., & Smith, S. C.
Affiliations
  • AACC International (US)
  • National Lipid Association (US)
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2016-07
Volume
68
Issue
1
Pages
92-125
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2016.03.519
OpenAlex
W2319057797
Semantic Scholar
1efd40ce44f07073487012e317c4511a64f3f506
Cited by
459
References
38
Citations by year
2026: 5 · 2025: 11 · 2024: 16 · 2023: 18 · 2022: 15 · 2021: 30 · 2020: 36 · 2019: 73 · 2018: 81 · 2017: 119 · 2016: 55
FWCI
21.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
American Heart Association
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
non-statin therapy, LDL cholesterol lowering, atherosclerotic cardiovascular disease, cardiovascular risk management, statin therapy, hypercholesterolemia, lipid-lowering therapy
MeSH terms
American Heart Association, Anticholesteremic Agents, Cardiology, Consensus Development Conferences as Topic, Consensus Statements as Topic, Decision Support Techniques, Humans, Cholesterol, LDL, United States, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Consensus, Atherosclerosis

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

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