EBM Tools for Practice: Guideline Fusion: A Reasonable Approach to Lipid Management

My old professor used to say that one could expand to mediocrity or shrink to excellence. There are now at least eight major organizations with cholesterol management guidelines,^{1,2,6,8,9,12,16,18} and another four organizations with special- population recommendations.^7,13,14,17 A recent review of this glut of guidelines concluded, “The number of published guidelines for management of LDL- related ASCVD risk and the substantive differences in recommendations may contribute to confusion among providers and lead to suboptimal management of at-risk patients.”² Maybe it’s time to “shrink to excellence.” In other words, take the recommendations of these various organizations and combine them into a tighter, simpler format.

What are the Basic Tenants of Lipid-Lowering Therapy?
1. The intensity of risk-reduction therapy should be adjusted to the patient’s absolute risk of an ASCVD event.

2. The extent that ASCVD risk is reduced is proportional to the degree of cholesterol lowering.

3. Lower is better in regards to low-density lipoprotein cholesterol (LDL-C).15  The Cholesterol Treatment Trialists’ meta- analysis showed that for every 38.7mg/dL drop in LDL-C, there was a 22 percent relative-risk reduction, with event reduction of similar magnitude across the spectrum of LDL-C levels >70mg/dL, and no difference in risk reduction between younger and older patients.⁴ A meta-analysis  of eight statin trials showed a linear reduction in risk down to LDL-C <50.5

4. There is a large inter-individual variation in the cholesterol-lowering response to statins. As such, LDL-C levels need to be monitored for the adequacy of a patient’s response and adherence to therapy.

5. Statins are the initial drug of choice. Statins and non-statins reduce risk in a one-to-one relationship with the degree of LDL-C lowering.^10,11

There is a major discordance in LDL-C goals between the American College of Cardiology/American Heart Association (ACC/AHA) 2013 guidelines and the NLA Recommendations for Patient-Centered Management of Dyslipiemia. Setting a goal of ≥50 percent LDL-C reduction for the high-risk population, as suggested by the ACC/AHA, is great for that segment with a low baseline LDL-C, but what about individuals with a high baseline LDL-C, such as 160-180mg/dL? A 50 percent drop puts them at 80-90mg/dL, which is still too high, as the studies above would suggest. Similarly, applying the NLA goal of LDL-C <70mg/dL to high risk patients with a low baseline LDL-C (i.e. LDL-C 95mg/dL) also results in inadequate risk reduction if the treatment goal is only to get LDL-C below 70mg/dL. Solution? Fuse the two recommendations as others have done.^6,8 For high-risk patients, set an LDL-C goal of <70mg/dL, or a greater-than-50 percent drop, whichever will result in a lower LDL- C. For moderate-risk patients, make the goal LDL-C <100, or a ≥ 30 to 49 percent drop, whichever gets LDL-C lower. This is consistent with the idea that lower is better, and the degree of risk reduction correlates with the amount of LDL-C reduction.

6. Atherosclerosis is a disease of particle numbers, not how much cholesterol the particles carry.^14,21 As such, some measure of LDL particle number should be included in the final lipid goal.

Fusing the Guidelines
Using the four groups identified by the ACC/AHA 2013 guidelines as a foundation, let’s combine/fuse recommendations.²

1. Clinical ASCVD. The LDL-C goal is >50 percent drop or <70mg/dL, whichever is lower. This fuses multiple recommendations.^1,3,6-9

2. Primary elevation of LDL-C ≥ 190 in patient’s ≥ 21 years old. These patients can develop  ASCVD without concomitant risk factors.³ The goal is LDL-C ≤100 or, if that’s not attainable, then a ≥50 percent reduction. This fuses recommendations.^1,3,8,9

3. Diabetics with LDL-C 70-189 and no clinical ASCVD. ASCVD is their major cause of morbidity and mortality, so be aggressive.⁸ Eliminate risk calculators.¹³ If they are <40 years old with no major ASCVD risk factors and LDLC<100mg/dL, it is reasonable to defer pharmacotherapy until risk is considered higher (> 40 years old). Otherwise, treat everyone. If they are >40 years old and have no risk factors, then set a goal of LDL-C<100 or a 30 to 49 percent drop. If there are risk factors, end-organ damage, or overt cardiovascular disease, no matter what the age, then aim for an LDL-C of <70 or a >50 percent drop. It’s a fusion of multiple recommendations.^1,3,6-8,13

4. Primary prevention with no diabetes or ASCVD, and LDL-C ≤ 189. The greatest confusion and debate is in considering this group. These patients need to be risk profiled, either by:

I. Statistical methods, using risk factors and risk calculators.^3,19,20 The NLA panel considers the threshold of high risk to be a Framingham risk score of ≥ 10 percent, or a Pooled Cohort Equation of ≥ 15 percent.¹

II. Identifying subclinical atherosclerosis, using a coronary calcium score. This latter approach appears to discriminate CV risk with a higher degree of accuracy.^20,23

The NLA goal for high-risk and modest- risk patients is an LDL-C of <100mg/d,  yet high-risk patients should have a more aggressive goal than moderate-risk patients. See Table 1 for fused recommendations.^1,3,6,8,12

Once the LDL-C is at goal, there should be some measurement of the LDL particle number since it is often a better marker of on-treatment risk prediction, and has been recommended by multiple guidelines (Table 2).^{1,6-9,12,14,16,21} 

Non-HDL-C has been recommended by some groups,^1,7-9,12 while others have suggested apoB1,^6-8,14 or LDL-P using nuclear magnetic reasonance.^1,16,21

Summary
First, risk profile the patient using the “fused guidelines” to determine the LDL goal.  Second, treat the LDL-C to goal using statin and non-statin as needed. Finally, check some measure of the LDL particle number to confirm adequacy of therapy.

Disclosure statement: Dr. Moran is a speaker for AstraZeneca, Merck, Amgen, and Sanofi-Regeneron.

References are listed on page 35 of the PDF.

The NLA invites members and guest authors to provide scientific and medical opinion, which do not necessarily reflect the policy of the Association.