New European Lipid Guidelines Take Aggressive Approach

September 01, 2019

New lipid guidelines from the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) have adopted an aggressive approach with new lower targets for low-density lipoprotein (LDL) reduction than seen before for most risk categories.

The new guidelines were released on August 31 at the ESC Congress 2019 and simultaneously published online in the European Heart Journal.

"The key strategy in these guidelines is lower is better, and while this has been generally recommended for some time, we are saying this still holds right down to very low levels of LDL," co-chair of the guidelines taskforce, Colin Baigent, FRCP, University of Oxford, United Kingdom, commented to | Medscape Cardiology.

"We wanted a simpler approach than before, and in the highest-risk patients we are recommending that LDL should be lowered as much as possible with really no lower limit." 

The guidelines give an LDL target of less than 1.4 mmol/L (<55 mg/dL) for patients at very high risk and an even lower target of less than 1.0 mmol/L (<40 mg/dL) for the very highest-risk patients with multiple recent events.

Baigent added: "For patients at very high risk (>10% risk of death over 10 years) we have recommended both a target LDL of 1.4 mmol/L and at least a 50% reduction.  This is much more aggressive than previous guidelines, which had a target of 1.8 mmol/L or a 50% reduction."

"The difference between the 'and' and the 'or' may appear to be a subtle change, but it could make a big difference to some patients. For example, if a very high-risk patient has an untreated LDL of 1.5 mmol/L, which is just above the 1.4 target, then the new recommendation of needing a 50% reduction in addition to getting below 1.4 would require LDL to be lowered much more — to 0.75 mmol/L."

"We did this because we know that the risk reduction is directly proportional to the magnitude of LDL lowering. If we want a good reduction in risk, we have to maximize the LDL reduction."

New LDL Targets Across CV Risk Categories

  • For very-high-risk patients (10-year risk of cardiovascular [CV] death >10%) an LDL cholesterol (LDL-C) reduction of at least 50% from baseline and an LDL-C goal of less than 1.4 mmol/L (< 55 mg/dL) are recommended.

  • For very high-risk patients who experience a second vascular event within 2 years (not necessarily of the same type as the first event) while taking maximally tolerated statin therapy, an LDL-C goal of less than 1.0 mmol/L (<40 mg/dL) may be considered.

  • For patients at high risk (10-year risk for CV death of 5% to 10%), an LDL-C reduction of 50% or greater from baseline and an LDL-C goal of less than 1.8 mmol/L (<70 mg/dL) may be considered.

  • For individuals at moderate risk (10-year risk for CV death of 1% to 5%), an LDL-C goal of less than 2.6 mmol/L (<100 mg/dL) should be considered.

  • For individuals at low risk (10-year risk for CV death <1%), an LDL-C goal of less than 3.0 mmol/L (<116 mg/dL) may be considered.


"We also recommend that patients should be treated aggressively with high-dose statins and with the option of adding ezetimibe and PCSK9 [proprotein convertase subtilisin/kexin type] inhibitors to achieve these targets. This is another big change from the previous guidelines," co-chair, François Mach, Geneva University Hospital, Switzerland, said.

"We wanted to go beyond what the US has done — we felt the evidence supported a more aggressive approach, although more evidence has become available since the last US guidelines were issued," Mach commented.

"The US approach of 'fire and forget' is not good enough," he added. "We need to keep reviewing the patient and keep measuring LDL levels to get them down as low as possible. Without this approach, patients tend to stop taking their statins."

"The new 1.4 mmol/L target for very high-risk patients is easy to justify using data from the latest meta-analyses and trials with high dose statins and PCSK9 inhibitors," Baigent noted. "The vast majority of patients can get to this level with high-dose statin plus ezetimibe. This is a cheap and safe combination. PCSK9 inhibitors will only need to be used in a very small proportion of patients."

No Distinction Between Primary and Secondary Prevention

The other major change in the new guidelines is the removal of the distinction between primary and secondary prevention. 

"What we've done is to make sure the recommendations are similar for a similar level of risk regardless of whether a patient has had a previous event," Baigent explained. "We have not distinguished between primary and secondary prevention; rather, risk is calculated the same way in both settings. 

"While secondary prevention patients will normally be at higher risk, a primary prevention patient could still be at high risk if they have multiple risk factors, and data show that the benefits of statins do not differ between primary and secondary prevention per se — rather, it is the level of risk that is important," he said.

The one exception to this is in the elderly. "While we have strengthened the recommendation for use of statins in the elderly in general, we have given a slightly weaker recommendation for primary prevention patients those aged over 75," he noted.

Emphasis on Statin Safety

The document has a new section emphasizing the safety of aggressive LDL lowering and of the statins. "There are no known adverse effects of very low LDL concentrations," it states. 

On the statins, it says: "While statins rarely cause serious muscle damage (myopathy, or rhabdomyolysis in the most severe cases), there is much public concern that statins may commonly cause less serious muscle symptoms. Such statin 'intolerance' is frequently encountered by practitioners and may be difficult to manage. However, placebo-controlled randomized trials have shown very clearly that true statin intolerance is rare, and that it is generally possible to institute some form of statin therapy (e.g. by changing the statin or reducing the dose) in the overwhelming majority of patients."

"We want to send a strong message to patients and physicians on this to try to keep patients on statins in the vast majority of cases," Mach said.  

Calcium Scores, Lp(a), ApoB for Risk Stratification

The guidelines also recommend for the first time the use of new tests to help identify higher-risk patients. These include both coronary artery calcium (CAC) imaging and biomarker tests.

"CAC score assessment with CT may be helpful in reaching decisions about treatment in people who are at moderate risk of atherosclerotic cardiovascular disease," the document notes. "Obtaining such a score may assist in discussions about treatment strategies in patients where the LDL-C goal is not achieved with lifestyle intervention alone and there is a question of whether to institute LDL-C-lowering treatment."

Mach commented: "If patients have a very low calcium score, then we can confidently say they have a very low risk of cardiovascular disease. This is a new recommendation for Europe and brings the guidelines into line with the US."

The guidelines also suggest that assessment of arterial (carotid or femoral) plaque burden on ultrasonography may also be informative in these circumstances.

On the biomarkers, the guidelines state: "ApoB may be a better measure of an individual's exposure to atherosclerotic lipoproteins, and hence its use may be particularly helpful for risk assessment in people where measurement of LDL-C underestimates this burden, such as those with high triglycerides, diabetes mellitus, obesity, or very low LDL-C."

It also recommends a single measurement of lipoprotein(a) [Lp(a)] in all individuals. "A one-off measurement of Lp(a) may help to identify people with very high inherited Lp(a) levels who may have a substantial lifetime risk of cardiovascular disease," the document notes. "It may also be helpful in further risk stratification of patients at high risk, in patients with a family history of premature cardiovascular disease, and to determine treatment strategies in people whose estimated risk is on the border of risk categories."

The guidelines also include a recommendation based on the recent REDUCE-IT trial of high-dose eicosapentaenoic acid (EPA) for patients with raised triglycerides (TG).    

 "We recommend measuring triglycerides, and based on the REDUCE-IT trial it is reasonable to use high-dose EPA (icosapent ethyl) in high-risk patients with TG levels between 1.5 and 5.6 mmol/L (135-499 mg/dL) despite statin treatment," Baigent said.

Well Received by US Experts

The new European guidelines were well received by two US experts contacted by | Medscape Cardiology.

Steve Nissen, MD, from the Cleveland Clinic in Ohio, said, "These are very thoughtful guidelines. The Europeans are being more open-minded than the Americans with these guidelines."

He elaborated: "I am very pleased with the 'lower is better' message and the recommended targets for LDL. The latest US guidelines are more focused on recommend thresholds for treatment, but the 'lower is better' philosophy coincides very precisely with what I believe to be right."

"Although specific LDL targets have not been mandated in trials, every trial has shown that lower LDL translates into better risk reduction, and the European guidelines have looked at the totality of the data and I think that is the right approach. Hats off to them on that," he added.

Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, Massachusetts, commented: "There is so much good content in this guideline. The writing committee must be commended for coming up with so many new actionable recommendations."

Bhatt said he agreed with the vast majority of the recommendations, "particularly the greater reliance on imaging and biomarkers for patients at low/moderate risk, and the greater emphasis on lowering LDL with multiple therapies in high-risk patients."

On the imaging recommendations, he pointed out that this is an area that has been controversial.

"These guidelines really validate these approaches to risk-stratify patients and personalize therapies, so that's a big conceptual change," Bhatt said. "I'm sure there will be some who object as there aren't randomized supporting data, but in reality, patients want these tests and in many cases are getting them anyway, so the horse is already out of the barn. We might as well try and figure out how we can incorporate them into our treatment algorithms in ways that are guideline supported. I do think this will be embraced," he added.

Bhatt also agreed that measuring Lp(a) would help identify a new cohort of patients who are very high risk and who right now are often missed. "This will have a large global impact."

Bhatt said the emphasis on statin safety was also welcome. "They are sending out good message that statin intolerance is overblown. We can usually get the vast majority of patients on statins if we are willing to play around with agent and dose."

The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website.

Eur Heart J. Published online August 31, 2019. Full text

European Society of Cardiology (ESC) Congress 2019.  Presented August 31, 2019.

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