2017 Focused Update of the 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

Abstract

In 2016, the American College of Cardiology published the first expert consensus decision pathway (ECDP) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk. Since the publication of that document, additional evidence and perspectives have emerged from randomized clinical trials and other sources, particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in secondary prevention of ASCVD. Most notably, the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial and SPIRE-1 and -2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), assessing evolocumab and bococizumab, respectively, have published final results of cardiovascular outcomes trials in patients with clinical ASCVD and in a smaller number of high-risk primary prevention patients. In addition, further evidence on the types of patients most likely to benefit from the use of ezetimibe in addition to statin therapy after acute coronary syndrome has been published. Based on results from these important analyses, the ECDP writing committee judged that it would be desirable to provide a focused update to help guide clinicians more clearly on decision making regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities. In the following summary table, changes from the 2016 ECDP to the 2017 ECDP Focused Update are highlighted, and a brief rationale is provided. The content of the full document has been changed accordingly, with more extensive and detailed guidance regarding decision making provided both in the text and in the updated algorithms. Revised recommendations are provided for patients with clinical ASCVD with or without comorbidities on statin therapy for secondary prevention. The ECDP writing committee judged that these new data did not warrant changes to the decision pathways and algorithms regarding the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C <190 mg/dL with or without diabetes mellitus or patients without ASCVD and LDL-C ≥190 mg/dL not due to secondary causes. Based on feedback and further deliberation, the ECDP writing committee down-graded recommendations regarding bile acid sequestrant use, recommending bile acid sequestrants only as optional secondary agents for consideration in patients intolerant to ezetimibe. For clarification, the writing committee has also included new information on diagnostic categories of heterozygous and homozygous familial hypercholesterolemia, based on clinical criteria with and without genetic testing. Other changes to the original document were kept to a minimum to provide consistent guidance to clinicians, unless there was a compelling reason or new evidence, in which case justification is provided.

Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials

“…Individuals with both DM and ASCVD have a particularly high risk of events, compared with individuals with either DM alone or ASCVD alone, yet are often sub‐optimally treated in clinical practice and may benefit from additional lipid‐lowering therapy beyond statins, because of elevated numbers of atherogenic particles 7, 8, 9, 10, 15. In this analysis of alirocumab Phase 3 trials in a population of very high‐risk patients with both ASCVD and DM, alirocumab treatment was shown to significantly reduce levels of LDL‐C and other atherogenic lipid parameters compared with placebo or ezetimibe controls; reductions were maintained throughout the duration of the trials (24‐104 weeks depending on trial) and overall safety was comparable to controls.…”

“…International guidelines for ASCVD risk management place individuals with DM and ASCVD in the highest risk category and recommend treatment with maximally tolerated statin therapy to reduce levels of low‐density lipoprotein cholesterol (LDL‐C), thereby reducing ASCVD risk 7, 8, 9, 10. This is supported by data from randomized clinical trials and meta‐analyses showing that treatment with statins reduces LDL‐C levels and ASCVD risk in individuals with DM 11, 12, 13.…”

“…The proportion of participants in these trials who experienced adverse events was comparable with that of controls. Based on these data, guidelines have been updated and now propose that adding ezetimibe and/or a PCSK9 inhibitor should be considered if the individual does not attain sufficient LDL‐C reduction with maximally tolerated statins alone, for example, if they have insufficient response to statin therapy or are unable to tolerate high or any doses of statins 7, 8, 9, 10, 15…”

“…Subgroup analyses have suggested similar efficacy and tolerability of alirocumab in individuals with and without DM 26, 30, 31, 32, 33. However, it is important to examine the effects of alirocumab in the specific subgroup of individuals with both DM and ASCVD who are at particularly high risk and may benefit from additional lipid‐lowering therapy beyond a statin 7, 8, 9, 10, 15. This post‐hoc analysis used pooled data from 9 ODYSSEY Phase 3 trials to evaluate the efficacy and safety of alirocumab in individuals with both DM and ASCVD.…”

National Trends in Nonstatin Use and Expenditures Among the US Adult Population From 2002 to 2013: Insights From Medical Expenditure Panel Survey

“…This was highlighted in the 2013 American Heart Association/American College of Cardiology guidelines for cholesterol management, which reflected weak evidence for nonstatin medications observed by several randomized controlled trials, including ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression),3 AIM‐HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcome),4 and ACCORD (Action to Control Cardiovascular Risk in Diabetes) 5. However, a recently published American College of Cardiology expert consensus document, written after the publication of IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)6 and FOURIER (Further Cardiovascular Outcomes Research With PCK9 Inhibition in Subjects With Elevated Risk),7 provides clinical guidance for nonstatin use but noted that the evidence base for the various agents is heterogeneous given that several medications in this class such as niacin, fibrates, and bile acid sequestrants lack strong contemporary evidence 8. However, to date, time trends in the utilization of nonstatin use and associated expenditure at a national level remain unknown.…”