The Latest Incarnation of the Blood Cholesterol Management Guideline 2018: Numbers Matter, Lower LDL-C is better A Special Report From the American Heart Association and American College of Cardiology

The AHA/ACC 2018 guideline on the management of blood cholesterol, endorsed by at least 10 other medical societies, was published online in the Journal of the American College of Cardiology and in Circulation to coincide with its grand unveiling at the American Heart Association (AHA) Scientific Sessions 2018 in Chicago, Illinois. 

This latest incarnation of the blood cholesterol management guideline since 2013 provided concrete guidance on the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, namely evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron). While the 2018 guideline retained the scoring system for 10-year atherosclerotic cardiovascular disease (ASCVD) risk, it was altered to include more population-based data than before.  In intermediate-risk primary prevention patients, coronary artery calcium (CAC) scores were retained for limited use as a potential “tie-breaker” in the statin-or-not decision process. The guideline recommended PCSK9 inhibitors, primarily for patients with familial hypercholesterolemia (FH), and for patients at very high ASCVD risk with elevated LDL-C despite the maximal use of statins and ezetimibe. In that latter group, initiation of nonstatin lipid-lowering therapy was to be considered for anyone with an LDL-C that had not fallen below 70 mg/dL.

The writing group of the 2018 guideline on management of blood cholesterol used primarily the Cholesterol Treatment Trialists’ (CTT) meta-analysis (S4.1-3, S4.1-4) of statin RCTs plus 4 other RCTs (S4.1-1, S4.1-2, S4.1-38, S4.1-39). Additional RCTs using non-statin drugs as add-ons to statin therapy were also included. The writers concluded that clinical Atherosclerotic Cardiovascular Disease (ASCVD) encompassed ACS, those with a history of MI, stable or unstable angina or coronary or other arterial revascularization, stroke, TIA or PAD including an aortic aneurysm, all of atherosclerotic origin. As a primary recommendation, high-intensity statin therapy was indicated for clinical ASCVD, but if this could not be used, moderate-intensity statin therapy could be initiated. The first goal was to achieve a ≥50% reduction in LDL-C levels, but if LDL-C levels remained ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin therapy, adding ezetimibe was reasonable. In patients >75 years of age with ASCVD, potential benefits versus adverse effects of statin therapy could be considered before initiation of statin therapy. Finally, in very high-risk patients with multiple high-risk clinical factors, ezetimibe could be added to maximally tolerated statin therapy. Furthermore, if LDL-C levels remained ≥70 mg/dL (≥1.8 mmol/L), adding a PCSK9 inhibitor was reasonable if the cost/benefit ratio was favorable. In patients with HF due to ischemic heart disease, moderate-intensity statins could be considered.

A list of key takeaways from the article includes the following:

1. In all individuals, emphasize a heart-healthy lifestyle across the life course.
2. In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy.
3. In very high-risk ASCVD, use an LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider the addition of nonstatins to statin therapy.
4. In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating 10-year ASCVD risk, begin high-intensity statin therapy without calculating 10- year ASCVD risk.
5. In patients 40 to 75 years of age with diabetes mellitus and LDL-C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk.
6. In adults, 40 to 75 years of age evaluated for primary ASCVD prevention, have a clinician-patient risk discussion before starting statin therapy.
7. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy.
8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7).
9. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL- 189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring CAC.
10. Assess adherence and percentage response to LDL-C–lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.

Expressing his optimism over the incorporation of all non statin therapies into the guideline recommendations, Dr. Christopher Cannon, Education Director, Cardiovascular Innovation at the Brigham and Women’s Hospital remarked, “We are all very happy to see the formal guideline to have the stepwise approach focussing on trying to make sure the patients are managed to get their LDLs down below 70.” He added, “The other big thing in the guideline is the advance in primary prevention. You start with AVSCD risk score to look at the spectrum but they included in the uncertain group (borderline risk), the notion of doing a calcium score to determine if there is or isn’t atherosclerosis.” Speaking of its importance, he stated, “The calcium score is a very powerful tool. There have been multiple studies over the recent years supporting it and it is really helpful in the guidelines, especially for younger patients where the calculated risk of an event in the next 10 years is low and yet, you have a sense that they have multiple risk factors and would like to get therapy going early.”

Speaking of the approach to statin-based therapy, the authors wrote, “The present guideline recommends a comprehensive approach to statin-associated symptoms. The clinician should reassess, rediscuss, and encourage rechallenge as the initial approach unless side effects are severe. Ongoing communication is integral to patient care, as is regular monitoring to check for adherence, adequacy of response, new associated symptoms, and reaffirmation of benefit.” Highlighting the implications of these guidelines, the writing committee, chaired by Scott M. Grundy, MD, Ph.D., University of Texas Southwestern Medical Center at Dallas, and co-chaired by Neil J. Stone, Northwestern University, Chicago, Illinois, stated, “Guideline publication does not guarantee guideline implementation. Healthcare delivery is complex, and barriers to guideline implementation can occur at the patient, clinician, health system, and health plan levels, leading to gaps in care. A more concerted effort, with multifaceted strategies aimed at the patient, clinician, health system, and health plan, is needed to overcome the barriers and achieve wider guideline implementation. The patient is a key player in successful guideline implementation, and the clinician-patient discussion is crucial to the successful initiation and continuation of guideline-directed management and therapy.”