- Email: [email protected]
Can We Eliminate Low-Density Lipoprotein Cholesterol-Related Cardiovascular Events Through More Aggressive Primary Prevention Therapy?
Accepted Manuscript Can we eliminate LDL-C-related cardiovascular events through more aggressive primary prevention therapy? G. B. John Mancini, MD, FRCPC, FACC, Robert A. Hegele, MD, FRCPC, FACP PII:
S0828-282X(18)30210-1
DOI:
10.1016/j.cjca.2018.02.027
Reference:
CJCA 2761
To appear in:
Canadian Journal of Cardiology
Received Date: 5 February 2018 Revised Date:
25 February 2018
Accepted Date: 25 February 2018
Please cite this article as: Mancini GBJ, Hegele RA, Can we eliminate LDL-C-related cardiovascular events through more aggressive primary prevention therapy?, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.02.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Can we eliminate LDL-C-related cardiovascular events through more aggressive primary prevention therapy?
RI PT
Running title: LDL-C-related Cardiovascular Events
G. B. John Mancini, MD, FRCPC, FACC, Robert A. Hegele, MD, FRCPC, FACP
SC
From the Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, CANADA, and the Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, London, Ontario, CANADA
G. B. John Mancini, MD, FRCPC, FACC Room 9111, Diamond Centre 2775 Laurel Street Vancouver, British Columbia V5Z 1M9
Fax: 604-785-5471 Email: [email protected]
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Phone: 604-875-5477
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Correspondence:
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EP
Word count : 3449 (with abstract)
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Intravascular levels of low density (LDL) cholesterol around 0.6 mmol/L or lower are likely to minimize, and perhaps eliminate, LDL cholesterol-related vascular toxicity while having no impact on essential, intracellular cholesterol homeostatic pathways, according to accumulated knowledge from basic
RI PT
science. Randomized clinical trials, observational reports and Mendelian randomization trials are also forcing a reconsideration of what "normal" LDL cholesterol means. Recent trials of secondary prevention have substantiated that such levels are safe and associated with a lowered risk of
SC
cardiovascular events (CVEs) compared with patients having higher levels of LDL cholesterol. Similarly, treatment to this low range is associated with regression and stabilization of established atherosclerosis.
M AN U
Primary prevention trials also show that low levels of LDL-C are safe and associated with lower risk of CVE through cholesterol lowering in adults with LDL-C ≥ 3.5 mmol/L or when levels are < 3.5 mmol/L in association with other cardiovascular risks. Although there are no randomized clinical trials of outcomes in familial hypercholesterolemia (FH) patients, such patients have very high, life-time risk of CVE, and
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registry studies show that LDL cholesterol reduction has nearly normalized their CVE rates. The possibility of FH should also be considered if LDL cholesterol is > 4.5 and > 4.0 mmol/L at ages 18 to 39 and < 18 years, respectively. Based on these convergent and internally consistent lines of evidence, this
EP
article speculates on a translational paradigm aimed at eliminating LDL cholesterol-related CVE through
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aggressive primary prevention strategies that are already proven and well accepted in principle.
ACCEPTED MANUSCRIPT
Preventing further cardiovascular events (CVE) after survival of an initial event - secondary prevention - is worthwhile. The pressure to efficiently complete clinical trials of innovative therapies within a finite budget and time frame has led many recent studies to focus on patients with prior CVE and an ever-increasing risk of future events, but who are simultaneously taking background therapy that
RI PT
is constantly improving. When translating the results into clinical practice, many guideline writers and regulators sometimes interpret the evidence base as literally as possible. Followed to its extreme logical conclusion, this approach would create a real life “ambulatory intensive care unit”, i.e. treating very high risk survivors of CVE with very expensive secondary prevention medications. But what is the role of
SC
primary prevention in this current environment? The message about aggressive risk factor modification in secondary prevention has clearly been accepted in mainstream clinical cardiology practice. Now, several recent and remarkable trials provoke some lateral thinking about primary prevention, with the
M AN U
tantalizing possibility that low density lipoprotein (LDL) cholesterol-related residual risk of CVE can be minimized if not eliminated.
The distinction between primary and secondary prevention materializes after aggregating data from clinical trials: slopes of the lines relating CVE and on-treatment levels of LDL cholesterol are steeper for secondary than primary prevention trials (Figure 1)1. However, both lines converge
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relentlessly towards the origin; event rates in both primary and secondary prevention contexts are infinitesimal when LDL cholesterol is very low. The recent Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) secondary prevention trial demonstrated that on treatment mean values of LDL cholesterol well below 1 mmol/L are both safe for
EP
patients, and associated with lower CVE compared to less aggressive LDL-lowering2. These results align with careful analyses of patients enrolled in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) primary prevention trial; conducted in individuals
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with the lowest entry level of baseline LDL cholesterol, using a potent statin intervention, achieving the lowest LDL cholesterol of primary prevention trials and the largest relative risk reduction of any3. As with FOURIER, in JUPITER, there were no safety concerns at levels of LDL cholesterol well below 1.3 mmol/L and optimal event reduction was observed in association with this very low level. These outcomes studies were mechanistically consistent with Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV), an imaging study, which demonstrated that LDL cholesterol lower than 1.5 mmol/L virtually guarantees either regression, deceleration of progression or lack of progression, all of which are associated with plaque stabilization and much lower CVE risk (Figure 2)4.
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The consistency of the observed safety and improved vascular health of these diverse trials are further concordant with longstanding physiological awareness that circulating, intravascular levels of LDL cholesterol of 0.6 mmol/L or lower are likely to minimize, and perhaps eliminate, LDL-related vascular toxicity while having no impact on essential, intracellular cholesterol homeostasis5-8. All these
RI PT
disparate lines of study and observation indicate that it would not be overly bold to assert that a
"normal" LDL cholesterol level is somewhere around 1.0 mmol/L (or lower). While laboratory reports may indicate that a "normal" LDL cholesterol is three-times this level or even higher, this designation should more correctly be considered as a "reference range" determined from the pathologically skewed
SC
distribution of LDL cholesterol values in westernized societies. It is likely not appropriate for either patients or health care providers to interpret that an LDL cholesterol level below the median in North America is "normal" from either a physiological or evolutionary perspective: the right-shifted LDL
M AN U
cholesterol distribution in affluent sedentary societies with easy access to calories reflects cultural norms and standards rather than optimal human physiology. Furthermore, this evolving concept of "normality" has implications for the timing of interventions to prevent CVE, likely with more emphasis on primary prevention and lower target LDL cholesterol levels9. More effective primary prevention should reduce both the future need for secondary prevention in survivors of first events and the
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incidence of fatal first events for which secondary prevention strategies are moot. Randomized clinical trials and other evidence such as observational and Mendelian randomization studies are forcing a reconsideration of what "normal" LDL cholesterol means9. The "experiment of nature" seen in patients with genetically high LDL cholesterol due to familial
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hypercholesterolemia (FH) provides further evidence that lower LDL cholesterol is better and lowest is best. There are no randomized clinical outcome trials of FH patients but much like secondary prevention patients, FH patients have very high, life-time risk of CVE secondary to chronic exposure of
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their vessels to LDL. Most lipidologists accept the analogy between “pack-years" of smoking and “mmol/L-years" of LDL cholesterol exposure. Moreover, long term cohort studies of FH patients support substantive CVE reduction with early statin use to reduce LDL cholesterol.10 Definitive genetic identification of FH is important for many reasons but practical management is ultimately driven by ageappropriate LDL-C levels: FH should be considered if LDL cholesterol is > 5.0, > 4.5 and > 4.0 mmol/L at ages > 40, 18 to 39 and < 18 years, respectively11. Once LDL cholesterol is treated in FH patients with statins, survival curves overlap those seen in the non-FH population, although based on the arguments above, LDL cholesterol levels in "normal" individuals may only be the minimal standard to which to aspire10, 12.
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What is the evidence for lipid lowering specifically in the context of primary prevention? Major primary prevention outcome trials and their main inclusion criteria are summarized in Table 1. They are organized into those that included patients with high or very high LDL cholesterol13-15, two that enrolled patients with “low normal” LDL cholesterol16 17 and those that did not specify any particular LDL
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cholesterol level for inclusion18-20. Irrespective of the LDL cholesterol criterion for inclusion, these were all positive trials. The fundamental conclusion is that “statin eligibility” for primary prevention reduces down clinically to identifying either a high level of LDL cholesterol or, if not high, the presence of at least another risk factor. In contrast, eligibility for active treatment in primary prevention in most current
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treatment guidelines is determined by a risk assessment algorithm, a process that was not actually evaluated in any trial. Additionally, none of these trials used evidence of existing, pre-clinical or
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asymptomatic atherosclerosis to identify eligibility for pharmacologic treatment.
Recognizing the potential benefit of early primary prevention, Ridker et al21 proposed a “hybrid” approach to lipid lowering therapy which first and foremost respected the main eligibility criteria of the primary prevention LDL cholesterol-lowering trials while liberalizing, as have most recent guidelines, the gender and slight age differences in these trials. Table 1, however, is enhanced by the Study of Heart and Renal Protection (SHARP)19 and Heart Outcomes Prevention Evaluation-3 (HOPE-3) trials20, and from
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this, an updated paradigm emerges and is summarized in Tables 2 to 4. Table 2 emphasizes the age and LDL cholesterol levels for which there is consensus or randomized clinical trial data supporting augmentation of healthy lifestyle, dietary, exercise and weight management with LDL cholesterol lowering drugs. The presence of additional risk factors or markers (Table 3) reduces the actionable
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threshold of LDL cholesterol. Algorithm-based risk assessment and imaging-based identification of preclinical or asymptomatic atherosclerosis are downgraded to a lower priority, since no randomized clinical trials so far uses these as eligibility criteria. We believe Table 4 simplifies the principles of
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therapy without engaging any hidden agenda, while remaining true to current best evidence. This proposed algorithm has several implications. First, patients with possible FH and at highest
lipid-related risk of CVE would be identified early based on age and LDL cholesterol, and would automatically warrant discussion of treatment well below the current guideline-recommended adult threshold of 5.0 mmol/L. This would require more consistent systematic LDL cholesterol screening, for instance starting in the post-pubertal age group. Second, in adults there is already RCT evidence to support treatment of isolated LDL cholesterol > 3.5 mmol/L without invoking algorithm-based risk assessment, in contrast to current recommendations to consider FH at the higher threshold of 5.0
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mmol/L . Third, occurrence of a CVE in an adult with an untreated LDL cholesterol > 3.5 mmol/L and no other risk factors would represent failure of either screening or treatment efforts, or both. Conversely, the rare instance of an initial or recurrent CVE in an adult with LDL-C < 1.0 mmol/L would shift attention to managing non-LDL cholesterol risk factors, such as different lipid species, perhaps including
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Lipoprotein(a), or non-lipid risk factors such as smoking, glycemia or blood pressure. Fourth, although impediments to achieving specific therapeutic goals are plentiful, there is now ample evidence that larger reductions of LDL cholesterol using safe interventions (i.e. statins, ezetimibe and PCSK9 inhibitors) are superior to smaller reductions for optimal prevention22, 23. Thus, defining the lowest feasible LDL
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cholesterol goal for a given patient is an imperative whose starting position is that a desirable LDL
cholesterol is below 1.0 mmol/L. This sort of informed “best effort” would respect both the science and
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the patient’s preferences and capabilities.
Much more work is needed to efficiently identify patients who would most benefit from early interventions, and also to make existing therapies, and emerging RCT-proven therapies both accessible and cost effective. Two important patient groups for evaluation, as mentioned, include those who do not fit the inclusion criteria of existing studies but are nonetheless identified as at risk either through algorithm-derived risk prediction or through detection of pre-clinical or asymptomatic atherosclerosis.
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Such studies would likely enrol a preponderance of young adults, including post-pubertal subjects. The feasibility of such trials may be daunting. While awaiting results of such future studies, there is still much that can potentially be done now. Brown and Goldstein endured some criticism when they speculated perhaps prematurely that heart attacks might be “gone with the century”24 although their
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speculations at the time might now be considered prescient. Because nothing is more useless than unfulfilled potential, it’s time to capitalize on such potential using the knowledge we already have. Thus, we speculate that translation of available evidence, including both primary and secondary prevention
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trials, basic science and the principles of practice that are supported when evaluating young patients with possible FH, has the potential to eliminate LDL-cholesterol-related cardiovascular disease.
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Figure 1: Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions. Adapted from reference 1 with permission.
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Figure 2: Relationship between achieved LDL-C and percent atheroma volume. Adapted from reference 4 with permission.
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Table 1: Primary prevention trials and main inclusion criteria.
Men 45 – 73y
TEXCAPS
Postmenopausal women 55 – 73y
ASCOT LLA
Men and Women 40 – 79y
JUPITER
Men ≥ 50y Women ≥ 60y
SHARP
Men and women ≥ 40y
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AFCAPS
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Men 45 – 64y
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WOSCOPS
≥ 4.7
Low Cholesterol Trials Hypertension with ≥ 3 of: microalbuminuria/proteinuria, smoking, family history of CHD, T2DM, TC/HDL > 6, LVH, EKG abnormalities, previous TIA/Stroke, PAD) hs-CRP ≥ 2.0
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Men and postmenopausal women 40 – 70y
< 5.5
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MEGA
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Age and Gender
High Cholesterol Trials Non-LDL-C Eligibility Criteria Total Cholesterol Eligibility Criteria ≥ 5.7
No Cholesterol Eligibility Criteria Plasma creatinine 1.7 mg/dL in men or 1.5 mg/dL in women, whether receiving dialysis or not (eGFR < 60 ml/min/1.73m2).
LDL-C (and HDL-C) Eligibility Criteria
LDL-C ≥ 4.0 LDL-C ≥ 3.4 and HDL-C Men ≤ 1.16 Women ≤ 1.22 LDL-C < 3.5
LDL-C < 3.4
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T2DM and Retinopathy or Albuminuria or Smoking or Hypertension
Men ≥ 55y Women ≥ 65y
Family history of premature CVD in first degree relative or Increased WHR or
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HOPE 3
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Men and women 40 – 75y
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CARDS
Current or recent smoking within 5 y or Low HDL-C (Men < 1.0, Women < 1.3) or
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IFG/IGT/uncomplicated T2DM (on diet or single agent therapy) or
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CKD (eGFR < 60 or microalbuminuria)
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AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT - LLA, Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm; C, cholesterol; CARDS, Collaborative Atorvastatin Diabetes Study; CHD, Coronary Heart Disease; CKD, Chronic Kidney Disease; CVD, Cardiovascular Disease; eGFR, estimated Glomerular Filtration Rate; EKG, Electrocardiogram; HDL, High Density Lipoprotein; HOPE, Heart Outcomes Prevention Evaluation; hs-CRP, high sensitivity C Reactive Protein; IFG, Impaired Fasting Glucose; IGT, Impaired Glucose Tolerance; JUPITER, Justification for Use of statin in Prevention: an Intervention Trial Evaluating Rosuvastatin; LDL, Low Density Lipoprotein; LVH, Left Ventricular Hypertrophy; MEGA, Management of Elevated cholesterol in the primary prevention Group of Adult Japanese study; PAD, Peripheral Arterial Disease; SHARP, Study of Heart And Renal Protection; T2DM, Type 2 Diabetes Mellitus; TC, Total Cholesterol; TIA, Transient Ischemic Attack; WHR, Waist to Hip Ratio; WOSCOPS, West of Scotland COronary Prevention Study; y = years.
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≥ 3.5 ≥ 4.0 ≥ 4.5 Consider Add drug therapy adding drug therapy based on additional risk factors Consider adding drug Add drug therapy based on therapy additional risk factors Add drug therapy
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< 3.5 mmol/L Emphasize Healthy Lifestyle, Dietary, Exercise and Weight Goals
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Actionable LDL cholesterol thresholds Age <18 Emphasize Healthy Lifestyle, Dietary, Exercise and Weight 18 - 39 Goals
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Table 2: Proposed actionable levels of LDL-C based on randomized clinical trials in adults and based upon the possibility of Familial Hypercholesterolemia and high, lifelong LDL-C-related risks in younger patients
≥ 40
Consider adding drug therapy based on additional risk factors Consider co-morbidities and non-CV health priorities before considering drug therapy
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≥ 75
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Table 3: Non LDL-C features that suggest utility of pharmacologic therapy.
Additional Risk Factors and Risk Markers Evaluated in Randomized Clinical Trials:
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Clinical atherosclerotic cardiovascular disease (CVD) Family history of premature CVD Diabetes, impaired fasting glucose, impaired glucose tolerance Increased waist-to-hip ratio
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Low HDL cholesterol or ratio of total to HDL cholesterol > 6 Hypertension
Chronic kidney disease Smoking (current or recent, within 5 years) Elevated high sensitivity C-reactive protein
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Left ventricular hypertrophy
Additional Features of Potential Value in Shared Decision-making:
Algorithm-generated moderate or high, short- or long-term CVD event rate
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Evidence of premature or pre-clinical atherosclerosis
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Table 4: Considerations for targets, goals and therapies in shared decision making.
Target of Therapy: LDL cholesterol if triglycerides < 1.5 mmol/L, otherwise consider non-HDL cholesterol or apolipoprotein B
Minimal goal: 30% reduction General goal: 50% reduction Regression goal: LDL cholesterol < 1.5 mmol/L Physiologically ideal goal (“normal LDL”): LDL cholesterol < 1.0 mmol/L
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Goals of Targeting LDL cholesterol Therapy (Shared Decision-making; Encourage Lowest, Feasible Goal):
Drug Therapies to Achieve Lowest Feasible LDL cholesterol Goal:
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1. Statin monotherapy at maximally tolerated doses 2. Maximally tolerated statin plus a second agent (ezetimibe or PCSK9 inhibitor) 3. Consider triple or more complex therapy using drugs other than statins, ezetimibe or PCSK9 inhibitor, only in concert with specialists in lipid and CV risk management
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References
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7. 8.
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Silverman MG, Ference BA, Im K, et al. Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Metaanalysis. JAMA. 2016;316:1289-1297. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376:1713-1722. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol. 2011;57:1666-1675. Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016;316:2373-2384. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34-47. Dietschy JM, Turley SD, Spady DK. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 1993;34:1637-1659. Olsson AG, Angelin B, Assmann G, et al. Can LDL cholesterol be too low? Possible risks of extremely low levels. J Intern Med. 2017;281:534-553. Masana L, Girona J, Ibarretxe D, et al. Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels-The zero-LDL hypothesis. J Clin Lipidol. 2018. DOI: 10.1016/j.jacl.2017.12.018 Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38:2459-2472. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008;337:a2423. Genest J, Hegele RA, Bergeron J, et al. Canadian Cardiovascular Society position statement on familial hypercholesterolemia. Can J Cardiol. 2014;30:1471-1481. Defesche JC, Gidding SS, Harada-Shiba M, Hegele RA, Santos RD, Wierzbicki AS. Familial hypercholesterolaemia. Nat Rev Dis Primers. 2017;3:17093. Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006;368:1155-1163. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-1307. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.
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Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181-2192. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374:2021-2031. Ridker PM, Rose L, Cook NR. A proposal to incorporate trial data into a hybrid ACC/AHA algorithm for the allocation of statin therapy in primary prevention. J Am Coll Cardiol. 2015;65:942-948. Mortensen MB, Nordestgaard BG. Comparison of Five Major Guidelines for Statin Use in Primary Prevention in a Contemporary General Population. Ann Intern Med. 2018;168:85-92. Mancini G. Comparison shopping: Guidelines for statins for primary prevention of cardiovascular disease. Ann Intern Med. 2018;168:145-146. Brown MS, Goldstein JL. Heart attacks: gone with the century? Science. 1996;272:629.
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S0828-282X(18)30210-1
DOI:
10.1016/j.cjca.2018.02.027
Reference:
CJCA 2761
To appear in:
Canadian Journal of Cardiology
Received Date: 5 February 2018 Revised Date:
25 February 2018
Accepted Date: 25 February 2018
Please cite this article as: Mancini GBJ, Hegele RA, Can we eliminate LDL-C-related cardiovascular events through more aggressive primary prevention therapy?, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.02.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Can we eliminate LDL-C-related cardiovascular events through more aggressive primary prevention therapy?
RI PT
Running title: LDL-C-related Cardiovascular Events
G. B. John Mancini, MD, FRCPC, FACC, Robert A. Hegele, MD, FRCPC, FACP
SC
From the Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, CANADA, and the Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, London, Ontario, CANADA
G. B. John Mancini, MD, FRCPC, FACC Room 9111, Diamond Centre 2775 Laurel Street Vancouver, British Columbia V5Z 1M9
Fax: 604-785-5471 Email: [email protected]
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Phone: 604-875-5477
M AN U
Correspondence:
AC C
EP
Word count : 3449 (with abstract)
ACCEPTED MANUSCRIPT
Intravascular levels of low density (LDL) cholesterol around 0.6 mmol/L or lower are likely to minimize, and perhaps eliminate, LDL cholesterol-related vascular toxicity while having no impact on essential, intracellular cholesterol homeostatic pathways, according to accumulated knowledge from basic
RI PT
science. Randomized clinical trials, observational reports and Mendelian randomization trials are also forcing a reconsideration of what "normal" LDL cholesterol means. Recent trials of secondary prevention have substantiated that such levels are safe and associated with a lowered risk of
SC
cardiovascular events (CVEs) compared with patients having higher levels of LDL cholesterol. Similarly, treatment to this low range is associated with regression and stabilization of established atherosclerosis.
M AN U
Primary prevention trials also show that low levels of LDL-C are safe and associated with lower risk of CVE through cholesterol lowering in adults with LDL-C ≥ 3.5 mmol/L or when levels are < 3.5 mmol/L in association with other cardiovascular risks. Although there are no randomized clinical trials of outcomes in familial hypercholesterolemia (FH) patients, such patients have very high, life-time risk of CVE, and
TE D
registry studies show that LDL cholesterol reduction has nearly normalized their CVE rates. The possibility of FH should also be considered if LDL cholesterol is > 4.5 and > 4.0 mmol/L at ages 18 to 39 and < 18 years, respectively. Based on these convergent and internally consistent lines of evidence, this
EP
article speculates on a translational paradigm aimed at eliminating LDL cholesterol-related CVE through
AC C
aggressive primary prevention strategies that are already proven and well accepted in principle.
ACCEPTED MANUSCRIPT
Preventing further cardiovascular events (CVE) after survival of an initial event - secondary prevention - is worthwhile. The pressure to efficiently complete clinical trials of innovative therapies within a finite budget and time frame has led many recent studies to focus on patients with prior CVE and an ever-increasing risk of future events, but who are simultaneously taking background therapy that
RI PT
is constantly improving. When translating the results into clinical practice, many guideline writers and regulators sometimes interpret the evidence base as literally as possible. Followed to its extreme logical conclusion, this approach would create a real life “ambulatory intensive care unit”, i.e. treating very high risk survivors of CVE with very expensive secondary prevention medications. But what is the role of
SC
primary prevention in this current environment? The message about aggressive risk factor modification in secondary prevention has clearly been accepted in mainstream clinical cardiology practice. Now, several recent and remarkable trials provoke some lateral thinking about primary prevention, with the
M AN U
tantalizing possibility that low density lipoprotein (LDL) cholesterol-related residual risk of CVE can be minimized if not eliminated.
The distinction between primary and secondary prevention materializes after aggregating data from clinical trials: slopes of the lines relating CVE and on-treatment levels of LDL cholesterol are steeper for secondary than primary prevention trials (Figure 1)1. However, both lines converge
TE D
relentlessly towards the origin; event rates in both primary and secondary prevention contexts are infinitesimal when LDL cholesterol is very low. The recent Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) secondary prevention trial demonstrated that on treatment mean values of LDL cholesterol well below 1 mmol/L are both safe for
EP
patients, and associated with lower CVE compared to less aggressive LDL-lowering2. These results align with careful analyses of patients enrolled in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) primary prevention trial; conducted in individuals
AC C
with the lowest entry level of baseline LDL cholesterol, using a potent statin intervention, achieving the lowest LDL cholesterol of primary prevention trials and the largest relative risk reduction of any3. As with FOURIER, in JUPITER, there were no safety concerns at levels of LDL cholesterol well below 1.3 mmol/L and optimal event reduction was observed in association with this very low level. These outcomes studies were mechanistically consistent with Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV), an imaging study, which demonstrated that LDL cholesterol lower than 1.5 mmol/L virtually guarantees either regression, deceleration of progression or lack of progression, all of which are associated with plaque stabilization and much lower CVE risk (Figure 2)4.
ACCEPTED MANUSCRIPT
The consistency of the observed safety and improved vascular health of these diverse trials are further concordant with longstanding physiological awareness that circulating, intravascular levels of LDL cholesterol of 0.6 mmol/L or lower are likely to minimize, and perhaps eliminate, LDL-related vascular toxicity while having no impact on essential, intracellular cholesterol homeostasis5-8. All these
RI PT
disparate lines of study and observation indicate that it would not be overly bold to assert that a
"normal" LDL cholesterol level is somewhere around 1.0 mmol/L (or lower). While laboratory reports may indicate that a "normal" LDL cholesterol is three-times this level or even higher, this designation should more correctly be considered as a "reference range" determined from the pathologically skewed
SC
distribution of LDL cholesterol values in westernized societies. It is likely not appropriate for either patients or health care providers to interpret that an LDL cholesterol level below the median in North America is "normal" from either a physiological or evolutionary perspective: the right-shifted LDL
M AN U
cholesterol distribution in affluent sedentary societies with easy access to calories reflects cultural norms and standards rather than optimal human physiology. Furthermore, this evolving concept of "normality" has implications for the timing of interventions to prevent CVE, likely with more emphasis on primary prevention and lower target LDL cholesterol levels9. More effective primary prevention should reduce both the future need for secondary prevention in survivors of first events and the
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incidence of fatal first events for which secondary prevention strategies are moot. Randomized clinical trials and other evidence such as observational and Mendelian randomization studies are forcing a reconsideration of what "normal" LDL cholesterol means9. The "experiment of nature" seen in patients with genetically high LDL cholesterol due to familial
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hypercholesterolemia (FH) provides further evidence that lower LDL cholesterol is better and lowest is best. There are no randomized clinical outcome trials of FH patients but much like secondary prevention patients, FH patients have very high, life-time risk of CVE secondary to chronic exposure of
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their vessels to LDL. Most lipidologists accept the analogy between “pack-years" of smoking and “mmol/L-years" of LDL cholesterol exposure. Moreover, long term cohort studies of FH patients support substantive CVE reduction with early statin use to reduce LDL cholesterol.10 Definitive genetic identification of FH is important for many reasons but practical management is ultimately driven by ageappropriate LDL-C levels: FH should be considered if LDL cholesterol is > 5.0, > 4.5 and > 4.0 mmol/L at ages > 40, 18 to 39 and < 18 years, respectively11. Once LDL cholesterol is treated in FH patients with statins, survival curves overlap those seen in the non-FH population, although based on the arguments above, LDL cholesterol levels in "normal" individuals may only be the minimal standard to which to aspire10, 12.
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What is the evidence for lipid lowering specifically in the context of primary prevention? Major primary prevention outcome trials and their main inclusion criteria are summarized in Table 1. They are organized into those that included patients with high or very high LDL cholesterol13-15, two that enrolled patients with “low normal” LDL cholesterol16 17 and those that did not specify any particular LDL
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cholesterol level for inclusion18-20. Irrespective of the LDL cholesterol criterion for inclusion, these were all positive trials. The fundamental conclusion is that “statin eligibility” for primary prevention reduces down clinically to identifying either a high level of LDL cholesterol or, if not high, the presence of at least another risk factor. In contrast, eligibility for active treatment in primary prevention in most current
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treatment guidelines is determined by a risk assessment algorithm, a process that was not actually evaluated in any trial. Additionally, none of these trials used evidence of existing, pre-clinical or
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asymptomatic atherosclerosis to identify eligibility for pharmacologic treatment.
Recognizing the potential benefit of early primary prevention, Ridker et al21 proposed a “hybrid” approach to lipid lowering therapy which first and foremost respected the main eligibility criteria of the primary prevention LDL cholesterol-lowering trials while liberalizing, as have most recent guidelines, the gender and slight age differences in these trials. Table 1, however, is enhanced by the Study of Heart and Renal Protection (SHARP)19 and Heart Outcomes Prevention Evaluation-3 (HOPE-3) trials20, and from
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this, an updated paradigm emerges and is summarized in Tables 2 to 4. Table 2 emphasizes the age and LDL cholesterol levels for which there is consensus or randomized clinical trial data supporting augmentation of healthy lifestyle, dietary, exercise and weight management with LDL cholesterol lowering drugs. The presence of additional risk factors or markers (Table 3) reduces the actionable
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threshold of LDL cholesterol. Algorithm-based risk assessment and imaging-based identification of preclinical or asymptomatic atherosclerosis are downgraded to a lower priority, since no randomized clinical trials so far uses these as eligibility criteria. We believe Table 4 simplifies the principles of
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therapy without engaging any hidden agenda, while remaining true to current best evidence. This proposed algorithm has several implications. First, patients with possible FH and at highest
lipid-related risk of CVE would be identified early based on age and LDL cholesterol, and would automatically warrant discussion of treatment well below the current guideline-recommended adult threshold of 5.0 mmol/L. This would require more consistent systematic LDL cholesterol screening, for instance starting in the post-pubertal age group. Second, in adults there is already RCT evidence to support treatment of isolated LDL cholesterol > 3.5 mmol/L without invoking algorithm-based risk assessment, in contrast to current recommendations to consider FH at the higher threshold of 5.0
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mmol/L . Third, occurrence of a CVE in an adult with an untreated LDL cholesterol > 3.5 mmol/L and no other risk factors would represent failure of either screening or treatment efforts, or both. Conversely, the rare instance of an initial or recurrent CVE in an adult with LDL-C < 1.0 mmol/L would shift attention to managing non-LDL cholesterol risk factors, such as different lipid species, perhaps including
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Lipoprotein(a), or non-lipid risk factors such as smoking, glycemia or blood pressure. Fourth, although impediments to achieving specific therapeutic goals are plentiful, there is now ample evidence that larger reductions of LDL cholesterol using safe interventions (i.e. statins, ezetimibe and PCSK9 inhibitors) are superior to smaller reductions for optimal prevention22, 23. Thus, defining the lowest feasible LDL
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cholesterol goal for a given patient is an imperative whose starting position is that a desirable LDL
cholesterol is below 1.0 mmol/L. This sort of informed “best effort” would respect both the science and
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the patient’s preferences and capabilities.
Much more work is needed to efficiently identify patients who would most benefit from early interventions, and also to make existing therapies, and emerging RCT-proven therapies both accessible and cost effective. Two important patient groups for evaluation, as mentioned, include those who do not fit the inclusion criteria of existing studies but are nonetheless identified as at risk either through algorithm-derived risk prediction or through detection of pre-clinical or asymptomatic atherosclerosis.
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Such studies would likely enrol a preponderance of young adults, including post-pubertal subjects. The feasibility of such trials may be daunting. While awaiting results of such future studies, there is still much that can potentially be done now. Brown and Goldstein endured some criticism when they speculated perhaps prematurely that heart attacks might be “gone with the century”24 although their
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speculations at the time might now be considered prescient. Because nothing is more useless than unfulfilled potential, it’s time to capitalize on such potential using the knowledge we already have. Thus, we speculate that translation of available evidence, including both primary and secondary prevention
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trials, basic science and the principles of practice that are supported when evaluating young patients with possible FH, has the potential to eliminate LDL-cholesterol-related cardiovascular disease.
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Figure 1: Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions. Adapted from reference 1 with permission.
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Figure 2: Relationship between achieved LDL-C and percent atheroma volume. Adapted from reference 4 with permission.
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Table 1: Primary prevention trials and main inclusion criteria.
Men 45 – 73y
TEXCAPS
Postmenopausal women 55 – 73y
ASCOT LLA
Men and Women 40 – 79y
JUPITER
Men ≥ 50y Women ≥ 60y
SHARP
Men and women ≥ 40y
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AFCAPS
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Men 45 – 64y
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WOSCOPS
≥ 4.7
Low Cholesterol Trials Hypertension with ≥ 3 of: microalbuminuria/proteinuria, smoking, family history of CHD, T2DM, TC/HDL > 6, LVH, EKG abnormalities, previous TIA/Stroke, PAD) hs-CRP ≥ 2.0
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Men and postmenopausal women 40 – 70y
< 5.5
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MEGA
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Age and Gender
High Cholesterol Trials Non-LDL-C Eligibility Criteria Total Cholesterol Eligibility Criteria ≥ 5.7
No Cholesterol Eligibility Criteria Plasma creatinine 1.7 mg/dL in men or 1.5 mg/dL in women, whether receiving dialysis or not (eGFR < 60 ml/min/1.73m2).
LDL-C (and HDL-C) Eligibility Criteria
LDL-C ≥ 4.0 LDL-C ≥ 3.4 and HDL-C Men ≤ 1.16 Women ≤ 1.22 LDL-C < 3.5
LDL-C < 3.4
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T2DM and Retinopathy or Albuminuria or Smoking or Hypertension
Men ≥ 55y Women ≥ 65y
Family history of premature CVD in first degree relative or Increased WHR or
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HOPE 3
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Men and women 40 – 75y
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CARDS
Current or recent smoking within 5 y or Low HDL-C (Men < 1.0, Women < 1.3) or
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IFG/IGT/uncomplicated T2DM (on diet or single agent therapy) or
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CKD (eGFR < 60 or microalbuminuria)
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AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT - LLA, Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm; C, cholesterol; CARDS, Collaborative Atorvastatin Diabetes Study; CHD, Coronary Heart Disease; CKD, Chronic Kidney Disease; CVD, Cardiovascular Disease; eGFR, estimated Glomerular Filtration Rate; EKG, Electrocardiogram; HDL, High Density Lipoprotein; HOPE, Heart Outcomes Prevention Evaluation; hs-CRP, high sensitivity C Reactive Protein; IFG, Impaired Fasting Glucose; IGT, Impaired Glucose Tolerance; JUPITER, Justification for Use of statin in Prevention: an Intervention Trial Evaluating Rosuvastatin; LDL, Low Density Lipoprotein; LVH, Left Ventricular Hypertrophy; MEGA, Management of Elevated cholesterol in the primary prevention Group of Adult Japanese study; PAD, Peripheral Arterial Disease; SHARP, Study of Heart And Renal Protection; T2DM, Type 2 Diabetes Mellitus; TC, Total Cholesterol; TIA, Transient Ischemic Attack; WHR, Waist to Hip Ratio; WOSCOPS, West of Scotland COronary Prevention Study; y = years.
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≥ 3.5 ≥ 4.0 ≥ 4.5 Consider Add drug therapy adding drug therapy based on additional risk factors Consider adding drug Add drug therapy based on therapy additional risk factors Add drug therapy
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< 3.5 mmol/L Emphasize Healthy Lifestyle, Dietary, Exercise and Weight Goals
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Actionable LDL cholesterol thresholds Age <18 Emphasize Healthy Lifestyle, Dietary, Exercise and Weight 18 - 39 Goals
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Table 2: Proposed actionable levels of LDL-C based on randomized clinical trials in adults and based upon the possibility of Familial Hypercholesterolemia and high, lifelong LDL-C-related risks in younger patients
≥ 40
Consider adding drug therapy based on additional risk factors Consider co-morbidities and non-CV health priorities before considering drug therapy
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≥ 75
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Table 3: Non LDL-C features that suggest utility of pharmacologic therapy.
Additional Risk Factors and Risk Markers Evaluated in Randomized Clinical Trials:
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Clinical atherosclerotic cardiovascular disease (CVD) Family history of premature CVD Diabetes, impaired fasting glucose, impaired glucose tolerance Increased waist-to-hip ratio
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Low HDL cholesterol or ratio of total to HDL cholesterol > 6 Hypertension
Chronic kidney disease Smoking (current or recent, within 5 years) Elevated high sensitivity C-reactive protein
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Left ventricular hypertrophy
Additional Features of Potential Value in Shared Decision-making:
Algorithm-generated moderate or high, short- or long-term CVD event rate
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Evidence of premature or pre-clinical atherosclerosis
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Table 4: Considerations for targets, goals and therapies in shared decision making.
Target of Therapy: LDL cholesterol if triglycerides < 1.5 mmol/L, otherwise consider non-HDL cholesterol or apolipoprotein B
Minimal goal: 30% reduction General goal: 50% reduction Regression goal: LDL cholesterol < 1.5 mmol/L Physiologically ideal goal (“normal LDL”): LDL cholesterol < 1.0 mmol/L
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Goals of Targeting LDL cholesterol Therapy (Shared Decision-making; Encourage Lowest, Feasible Goal):
Drug Therapies to Achieve Lowest Feasible LDL cholesterol Goal:
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1. Statin monotherapy at maximally tolerated doses 2. Maximally tolerated statin plus a second agent (ezetimibe or PCSK9 inhibitor) 3. Consider triple or more complex therapy using drugs other than statins, ezetimibe or PCSK9 inhibitor, only in concert with specialists in lipid and CV risk management
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