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Elevated serum cholesterol is one of the world’s most common and modifiable risk factors for cardiovascular disease (CVD). In the 5 years since the release of the 2013 American Heart Association/American College of Cardiology (AHA/ACC) guideline for lipid management,1 there have been multiple advances in lipid biology, epidemiology, and therapeutic clinical trials. This wealth of new evidence led the AHA/ACC to release a major revision of the lipid practice recommendations in 2018.2 Overall, the new guidelines are more evidence based and personalized than in the past but also more complex. The full content of the new lipid guidelines is contained in a well-referenced 65-page document and summarized in 10 succinct top messages highlighted in this issue of JAMA.3
As with prior versions, the 2018 cholesterol guideline recommends statins as the bedrock therapy for all patients with clinical CVD. However, the guideline also proposes that clinicians should further identify patients with CVD who have very high-risk for future events based on recent CVD events, polyvascular disease, and other high-risk CVD risk factors, defined as age ≥65 years, heterozygous familial hypercholesterolemia, history of coronary artery bypass graft surgery or percutaneous coronary intervention outside of the major ASCVD event(s), diabetes, hypertension, chronic kidney disease (estimated glomerular filtration rate of 15-59 mL/min/1.73 m2), current smoking, persistently elevated low-density lipoprotein cholesterol (LDL-C; ≥100 mg/dL [≥2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe, and history of congestive heart failure. Individuals at high risk are recommended to be treated to a target LDL-C goal of less than 70 mg/dL. For those in whom this goal is not achieved with high-dose statins, the guideline recommends the addition of nonstatin therapy (either ezetimibe or a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor). In choosing between these nonstatin options, the guideline favors ezetimibe (a generic medication) as next-in-line therapy because PCSK9 inhibitors were deemed to have “low economic value based on their 2018 prices.”2
The stratification of patients with known CVD and more aggressive treatment for those at very high risk are needed changes in the guidelines. These changes emphasize the importance of achieving target lipid goals, integrate the value of combination statin-nonstatin therapies for those at highest risk, and are consistent with a wealth of clinical trial data. The guideline writers also explicitly considered value in their new treatment recommendation, one of the first times this has been done in guideline statements, and increasingly important as US health care costs continue their inexorable rise. Even though 2 recent trials have now demonstrated that PCSK9 therapy added to high-dose statins is safe and effective to reduce major cardiovascular events,4,5 the drugs were initially priced very high, reducing their cost-effectiveness estimates (>$100 000 per quality-adjusted life-year). Some may argue that guideline writers should not explicitly consider cost in treatment decisions, but this seems unavoidable from a societal viewpoint. Furthermore, the decision by the AHA/ACC guideline writers to consider cost likely put needed pressure on the drugmakers to lower drug prices. The challenge for incorporating cost-effectiveness into the guideline is that prices can change quickly. Even before the release of the 2018 guideline, the costs of PCSK9 inhibitors were reduced by more than 50%, making prior cost-effectiveness estimates and the nonstatins treatment algorithms dated.
For primary prevention, the 2018 guideline suggests that treatment recommendations should be based on a patient’s overall CVD risk profile, estimated using the 10-year Pooled Cohort Equations CV Risk Calculator.2 The current guideline further personalized these CVD risk estimates for those with inflammatory illnesses, preeclampsia, early menopause, and South Asian ethnicity. The guideline also stresses that patients should play a central role in the decision-making process. For patients who remain unsure whether to initiate therapy after clinical risk assessment, the guideline suggests that coronary artery calcium scores could be useful.6 A high calcium score can encourage patients to consider therapy, whereas the absence of coronary calcium predicts lower risk of CVD and may lead to a decision for lifestyle modification rather than drug therapy. Additionally, the 2018 guideline clarifies that it is important to monitor response to drug therapy between 4 and 12 weeks after starting therapy and annually thereafter to ensure adherence.
Overall, the 2018 guideline addresses a diverse spectrum of clinical factors and selective imaging to inform CVD risk assessment. This strategy will lead to more precise patient estimates. Yet applying the maze of branching guideline algorithms will be more challenging for clinicians to implement. In the past, clinicians could use simple heuristic cutoffs (based on LDL-C levels, 10-year risk estimates, or both) to determine which patients needed lipid treatment. Now clinicians also must consider multiple subgroups based on cholesterol levels, age, presence or absence of CVD, diabetes, other traditional and nontraditional CVD clinical risk factors, and perhaps even imaging studies to determine whether and what treatment to recommend.
The 2018 guideline also places considerable emphasis on engaging patients in the process. Incorporation of an individual’s values in treatment decisions is not only the right thing to do but can also increase the likelihood of adherence to the selected strategy. The challenge for shared decision making, however, is how to convey therapeutic risks and benefits in a manner that is accurate, objective, and understandable to a patient. The choice of risk estimate, time horizon, and visual display can have significant influence on patients’ impressions of their disease risk and their willingness to consider treatment.7
Moving forward, several remaining gaps in evidence need to be filled. Among individuals aged 20 to 40 years, the 2018 guideline recommends starting statin therapy only in those with LDL-C greater than 160 mg/dL and a family history of premature atherosclerosis or have high lifetime estimated CVD risk. Epidemiological studies demonstrate clearly that the number of years of exposure to elevated serum LDL-C is predictive of risk of CVD.8 Thus, many young people with elevated LDL-C levels (eg, 140-160 mg/dL) have a high lifetime risk of CVD and should be considered for statin therapy. Similarly, individuals older than 75 years have been historically understudied, and the guideline is appropriately cautious in treatment recommendations pending upcoming clinical trials directed specifically at elderly persons. Moreover, the guideline mostly focuses on therapies that lower LDL-C. However, immediately after the release of the guideline, the results of the REDUCE-IT trial raised the hope that lowering other lipid components including triglycerides may improve downstream outcomes in select populations.9
In conclusion, the 2018 lipid guideline represents a significant and positive step forward for cardiovascular disease prevention. While no guideline is perfect, if the algorithms in these new guidelines were followed, thousands if not millions of people worldwide each year would be able to avoid CVD events. However, the uptake and translation of guidelines into practice has been historically poor. Even in the United States, which spends more on health care than any other country, more than half of all residents did not meet the 2013 less stringent lipid management guidelines recommendations.10 Moving forward, the United States will need to do better to improve individual and population health. Ideally, the increased use of electronic medical records, computer-aided clinical decision support, and team-based care models could assist in the appropriate application of these algorithms for management of cholesterol levels in community practice.
Corresponding Author: Eric Peterson, MD, MPH, Duke University Medical Center, PO Box 17969, Durham, NC 27715 (firstname.lastname@example.org).
Published Online: February 4, 2019. doi:10.1001/jama.2019.0045
Conflict of Interest Disclosures: Dr Peterson reported receiving grants and/or fees for consulting from Abiomed, Amgen, Bayer, Genentech, Merck, Novartis, Sanofi, Regeneron, Livongo, AstraZeneca, Janssen, Merck, and the Society of Thoracic Surgeons. No other disclosures were reported.
Peterson E, Greenland P. A New Personalized, Patient-Centric, and Cost-Conscious Guideline for Contemporary Cholesterol Management. JAMA. Published online February 04, 2019. doi:10.1001/jama.2019.0045
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