Sandbox: LDL guideline

2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway (ECDP) on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk

Summary of Changes in the 2017 Focused Update

Section	2016 ECDP	2017 ECDP Focused Update
Introduction	Included consideration of evidence from cardiovascular outcomes trials of ezetimibe, niacin, and niacin/laropiprant.	Includes consideration of new randomized clinical trial (RCT) data with the PCSK9 inhibitors, evolocumab and bococizumab.
Comment/Rationale: At the time of publication of the original 2016 ACC ECDP on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk, long-term cardiovascular outcomes trials were ongoing for both alirocumab and evolocumab, as well as for bococizumab, a PCSK9 inhibitor that is not U.S. Food and Drug Administration approved. Subsequently, the final results of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and SPIRE-1 and -2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events) cardiovascular outcomes trials were published in early 2017. Details of results are included in the updated Introduction section.
	2016 ECDP	2017 ECDP Focused Update
ECDP Algorithms	Thresholds for consideration of net ASCVD risk reduction benefit were percent reduction in LDL-C and may consider absolute LDL-C level in patients with clinical ASCVD, baseline LDL-C ≥190 mg/dL, and primary prevention. In patients with diabetes with or without clinical ASCVD, it was stated that the clinician may consider absolute LDL-C and/or non-HDL-C levels.	Thresholds for consideration of net ASCVD risk reduction are percent reduction in LDL-C and may consider absolute LDL-C or non-HDL-C levels for patients in each of the 4 statin benefit groups.
Comment/Rationale: The FOURIER trial of evolocumab included patients with clinical ASCVD with or without diabetes on statin dose equivalent of at least atorvastatin 20 mg who had either LDL-C ≥70 mg/dL or non–HDL-C ≥100 mg/dL. The ongoing ODYSSEY Outcomes trial of alirocumab includes patients with non–HDL-C ≥100 mg/dL. The SPIRE-2 trial of bococizumab included high-risk primary prevention patients (18.9%) and patients with familial hypercholesterolemia (7.0%) with LDL-C ≥100 mg/dL or non–HDL-C ≥130 mg/dL. In alignment with these inclusion criteria, the 2017 Focused Update includes both LDL-C and non–HDL-C thresholds for evaluation of net ASCVD risk reduction benefit when considering the addition of non-statin therapies for patients in each of the 4 statin benefit groups.
	2016 ECDP	2017 ECDP Focused Update
Adults ≥21 Years of Age With Clinical ASCVD, on Statin for Secondary Prevention, Baseline LDL-C 70–189 mg/dL	Thresholds for consideration of net ASCVD risk reduction benefit in patients with clinical ASCVD without comorbidities were $50% reduction in LDL-C and may consider LDL-C <100 mg/dL. Thresholds for patients with clinical ASCVD with comorbidities were ≥50% reduction in LDL-C and may consider LDL-C <70 mg/dL.	Thresholds for consideration of net ASCVD risk-reduction benefit are LDL-C reduction ≥50% and may consider LDL-C <70 mg/dL or non-HDL-C <100 mg/dL for all patients with clinical ASCVD and baseline LDL-C 70–189 mg/dL.
Comment/Rationale: The writing committee considered the results of the cardiovascular outcomes trials, IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) and FOURIER, demonstrating the safety and efficacy of the addition of ezetimibe or evolocumab to maximally tolerated statin therapy in patients with clinical ASCVD and on-statin-treatment LDL-C levels of approximately 70 mg/dL in IMPROVE-IT and 92 mg/dL in FOURIER. Based on consideration of all available evidence, the consensus of the writing committee members is that lower LDL-C levels are safe and optimal in patients with clinical ASCVD due to the increased risk of recurrent events.
	2016 ECDP	2017 ECDP Focused Update
Adults ≥21 Years of Age With Clinical ASCVD With comorbidities, on Statin for Secondary Prevention, Baseline LDL-C 70–189 mg/d–L	If a decision is made to proceed with the addition of non- statin therapy to maximally tolerated statin therapy, it is reasonable to consider the addition of ezetimibe as the initial agent and a PCSK9 inhibitor as the second agent.	If a decision is made to proceed with the addition of non- statin therapy to maximally tolerated statin therapy in patients with clinical ASCVD with comorbidities and baseline LDL-C 70–189 mg/dL, it is reasonable to consider the addition of either ezetimibe or a PCSK9 inhibitor based on considerations of the additional percent LDL-C reduction desired, patient preferences, costs, route of administration, and other factors. Clinicians should preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects and drug–drug interactions, and consider patient preferences. Considerations that may favor the initial choice of ezetimibe include: patients who require <25% additional lowering of LDL-C, patients with recent ACS <3 months, cost considerations with recent availability of generic ezetimibe and future cost savings, ease of use as oral agent with low pill burden, patient preferences, heart failure, hypertension, age >75 years, diabetes, stroke, CABG, PAD, eGFR <60 ml/min/1.73 m2, and smoking. If patients with clinical ASCVD and comorbidities require >25% additional lowering of LDL-C, a PCSK9 inhibitor may be preferred as the initial non-statin agent. The clinician–patient discussion should consider the extent of available scientific evidence for net ASCVD risk- reduction benefit, cost, administration by subcutaneous injection, every 14-day or monthly dosing schedule, and storage requirements (refrigeration).
Comment/Rationale: The results of FOURIER demonstrated that in high-risk patients with clinical ASCVD and additional risk factors, evolocumab treatment significantly reduced the risk of the primary endpoint (composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) (hazard ratio: 0.85; 95% confidence interval [CI]: 0.79 to 0.92, p<0.001) and the key secondary endpoint (composite of cardiovascular death, MI, or stroke) (hazard ratio: 0.80; 95% CI: 0.73 to 0.88; p<0.001). The magnitude of risk reduction in cardiovascular death, MI, or stroke appeared to increase over time, from 16% in the first year of follow-up to 25% beyond 1 year. See text for further details. The ongoing ODYSSEY Outcomes trial includes 18,600 post- ACS (4-52 weeks) patients on evidence-based statin therapy who are randomized to the addition of alirocumab or placebo. The primary endpoint is CHD death, MI, ischemic stroke, or hospitalization for unstable angina. The estimated study completion date is December 2017. A recent post-hoc analysis of IMPROVE-IT identified 9 clinical variables (congestive heart failure, hypertension, age >75 years, diabetes, stroke, CABG, PAD, eGFR <60 ml/min/1.73 m2, and smoking) that may help predict patients after ACS who have the greatest likelihood of benefit from the addition of ezetimibe to statin therapy following ACS.
	2016 ECDP	2017 ECDP Focused Update
Adults ≥21 Years of Age With Clinical ASCVD With Comorbidities, on Statin for Secondary Prevention, Baseline LDL-C 70–189 mg/dL	In patients with clinical ASCVD, comorbidities associated with increased risk of recurrent events included: diabetes, a recent (<3 months) ASCVD event, an ASCVD event while already taking a statin, poorly controlled other major ASCVD risk factors, elevated lipoprotein(a), CKD, symptomatic heart failure, maintenance hemodialysis, or baseline LDL-C ≥190 mg/dL not due to secondary causes.	The 2017 Focused Update also includes the following factors that may be considered for the identification of higher-risk patients with clinical ASCVD: age ≥65 years, prior MI or non-hemorrhagic stroke, current daily cigarette smoking, symptomatic PAD with prior MI or stroke, history of non-MI related coronary revascularization, residual coronary artery disease with ≥40% stenosis in ≥2 large vessels, HDL-C <40 mg/dL for men and <50 mg/dL for women, hs-CRP >2 mg/L, or metabolic syndrome.
Comment/Rationale: The results of FOURIER demonstrated that in high-risk patients with clinical ASCVD and additional risk factors, evolocumab treatment significantly reduced the risk of the primary endpoint (composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) (hazard ratio: 0.85; 95% CI: 0.79 to 0.92, p<0.001) and the key secondary endpoint (composite of cardiovascular death, MI, or stroke) (hazard ratio: 0.80; 95% CI: 0.73 to 0.88; p<0.001). The inclusion criteria in FOURIER were clinical ASCVD and at least 1 major risk factor (patients with age ≥65 years, prior MI or non-hemorrhagic stroke, current daily cigarette smoking, symptomatic PAD with prior MI or stroke) or 2 minor risk factors (history of non-MI related coronary revascularization, residual coronary artery disease with ≥40% stenosis in ≥2 large vessels, HDL-C <40 mg/dL for men and <50 mg/dL for women, hs-CRP >2 mg/L, or metabolic syndrome).
ACC indicates American College of Cardiology; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass graft; CI, confidence interval; CKD, chronic kidney disease; ECDP, expert consensus decision pathway; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high- sensitivity C-reactive protein; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PAD, peripheral arterial disease; PCSK9, proprotein convertase subtilisin/kexin 9; and RCT, randomized clinical trial.

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

Patient Populations Addressed and Factors and Interventions to Consider

PATIENT POPULATIONS ADDRESSED: 4 STATIN BENEFIT GROUP
Adults ≥21 years of age with clinical ASCVD, on statin for secondary prevention	Adults ≥21 years of age with baseline LDL-C ≥190 mg/dl (not due to secondary modifiable causes), on statin for primary prevention	Adults aged 40-75 years without clinical ASCVD but with diabetes and baseline LDL 70-189 mg/dl, on statin for primary prevention	Adults aged 40-75 years without clinical ASCVD or diabetes, with baseline LDL-C 70-189 mg/dl and an estimated 10-year risk for ASCVD of ≥7.5%, on statin for primary prevention.
FACTORS TO CONSIDER 1)Adherence and Lifestyle 2)Statin Intolerance 3)Control of other risk factors 4) Clinician-patient discussion regarding potential benefits, potential harms and patient preferences regarding addition of non-statin medications 5) Percentage LDL-C reduction (may consider absolute LDL-C level achieved) 6) Monitoring of response to therapy, adherence and life style.
OPTIONAL INTERVENTIONS TO CONSIDER 1) Referral to lipid specialist and registered dietitian nutritionist 2) Ezetimibe 3) PCSK9 Inhibitors 4) Mipomersen, lomitapide, LDL apheresis may be considered by limit specialist for patients with familial hypercholesterolemia.

Four Statin Benefit Groups and Major Recommendations

Patient Group	Major Recommendations
Adults aged ≥21 years with clinical ASCVD (including history of or current acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin)	1. For patients age ≤75 years, high-intensity statin (or moderate-intensity statin if not a candidate for high-intensity statin due to safety concerns) 2. For patients age >75 years, moderate-intensity statin
Adults aged ≥21 years with LDL-C ≥ 190 mg/dL (not due to modifiable secondary causes)	1. High-intensity statin therapy to achieve ≥50% reduction in LDL-C statin (or moderate-intensity statin if not a candidate for high-intensity statin due to safety concerns) 2. May consider combining statin and non-statin therapy to further reduce LDL-C 3. Cascade screening of close biologic relatives should be performed to identify others with the disease who would benefit from treatment.
Adults aged 40–75 years without ASCVD but with diabetes and with LDL-C 70–189 mg/dL	1. Moderate-intensity statin 2. If 10-year ASCVD risk ≥7.5%, consider high-intensity statin.
Adults aged 40–75 years without ASCVD or diabetes, and with LDL-C 70–189 mg/dL and an estimated 10-year risk for ASCVD of ≥7.5%	1. Estimate 10-year ASCVD risk using Pooled Cohort Equations (2): a. If ≥7.5%, moderate- or high-intensity statin; b. If ≥5 to <7.5%, consider moderate-intensity statin. 2. In selected individuals with 10-year ASCVD risk <5%, or age <40 or >75 years, individualize decisions based on presence of other high-risk features. 3. Before initiation of statin therapy for primary prevention, it is reasonable for clinicians and patients to engage in a discussion that considers the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions, as well as patient preferences for treatment.
ABI indicates ankle-brachial index; ACC, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcification; hs-CRP, high-sensitivity C-reactive protein; and LDL-C, low-density lipoprotein cholesterol.

Patient Populations Addressed: 4 Statin Benefit Group

Adults ≥21 years of age with clinical ASCVD, on statin for secondary prevention

Adults ≥21 years of age with baseline LDL-C ≥190 mg/dl (not due to secondary modifiable causes), on statin for primary prevention

Adults aged 40-75 years without clinical ASCVD but with diabetes and baseline LDL 70-189 mg/dl, on statin for primary prevention

Adults aged 40-75 years without clinical ASCVD or diabetes, with baseline LDL-C 70-189 mg/dl and an estimated 10-year risk for ASCVD of ≥7.5%, on statin for primary prevention

FACTORS TO CONSIDER - 1)Adherence and Lifestyle 2)Statin Intolerance 3)Control of other risk factors 3) Clinician-patient discussion regarding potential benefits, potential harms and patient preferences regarding addition of non-statin medications 4) Percentage LDL-C reduction (may consider absolute LDL-C level achieved) 5) Monitoring of response to therapy, adherence and life style

OPTIONAL INTERVENTIONS TO CONSIDER - 1) Referral to lipid specialist and registered dietitian nutritionist 2) Ezetimibe 3) PCSK9 Inhibitors 4) Mipomersen, lomitapide, LDL apheresis may be considered by limit specialist for patients with familial hypercholesterolemia.