EAS Lipid Guidance: Start High-risk Patients on Combo Drug

Liam Davenport

June 29, 2021

Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.

The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.

Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.

The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis.

Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance with theheart.org | Medscape Cardiology at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.

He explained that the motivation for creating the practical guidance was "very simple," and concerns something already embedded in the ESC/EAS guidelines, it's just that "people didn't notice" it.

Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels "you can get by starting with high-intensity therapy and/or starting with a combination therapy."

The guidelines, he said, suggest steps for achieving lipid control: begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.

Catapano added that, "having said that, at the beginning, you can guess by knowing how far you are from the goal as to whether a statin by itself with help you get" there.

If clinicians follow the new practical guidance of giving upfront combination statin–ezetimibe therapy in very-high-risk patients with high LDL-cholesterol levels, it will "save a lot of time, a lot of clinic visits, and will you get you to goal earlier."

He gave the example of a patient who has an LDL-cholesterol level of 190 mg/dL, who would be classified as being at very high risk. With the target goal of 55 mg/dL, "you would never be able to get them to goal only with a high-intensity statin."

The addition of ezetimibe to the regimen of this patient would have two advantages, Catapano said. The first is that "you get to goal more easily," and the second is that, with the drugs available as a single-pill combination, it "makes it easier for the patient to be compliant."

Consequently, there will be no "unnecessary back and forth," he said. "Some of these are young people. They go to work; one less visit is less time lost at work.

"This is a practical issue," he added. "It doesn't contradict the guidelines," it's about "everyday clinical practice."

Useful Between Updates

Responding to the guidance, Donald Lloyd-Jones, MD, president-elect of the American Heart Association (AHA), told theheart.org | Medscape Cardiology that "this kind of document can be useful in periods between updates of the formal guidelines."

New evidence comes out in between guidelines, and they "don't often provide us with all of the practical solutions needed for everyday guidance when we're dealing with individual patients with real-world problems."

Lloyd-Jones, who is chair of the Department of Preventive Medicine at the Northwestern University Feinberg School of Medicine, Chicago, said the 2019 ESC/EAS guidelines set "quite aggressive targets, particularly for LDL cholesterol…but didn't really provide much practical advice on how clinicians could get there for their patients."

"While this document doesn't completely address all patient groups, it does provide some good practical advice," recognizing that "if you need to get to a certain LDL target, it's unlikely you're going to get there with just a statin in certain types of patients," and "if you need a certain amount of LDL lowering, it's certainly reasonable to start upfront with a statin and ezetimibe and see how you do."

Crucially, Lloyd-Jones believes that the practical guidance does "flesh out some of the details the guidelines didn't address."

In terms of the aggressive LDL-cholesterol targets set out in the original guidelines, he said that "everyone agrees that lower is always better…and we've not get yet found a level that is too low."

Further, "we're certainly pushing patients lower and lower, especially with the use of PCSK9 inhibitors, so I think the general philosophy is consistent and correct," although "it's difficult to point to great evidence from clinical trials that specially says that 55 mg/dL or 40 mg/dL is the right target for a given group of patients."

"There's really very limited evidence for those specific numbers," Lloyd-Jones added, "but I think everyone agrees, especially for patients at higher risk, the lower we can get them the better. What really matters, and what this document starts to address, is how we achieve as low as possible, and I think there are some important considerations that they take into account."

Aside from how far patients need their LDL cholesterol lowered from baseline, there are issues like cost and patient preference for different types of medication, and these "weren't particularly well addressed in the guidelines," he added.

Scott D. Isaacs, MD, Secretary of the American Association of Clinical Endocrinologists (AACE), commented that the ESC/EAS recommendations echo the 2017 AACE/American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.

He said that both guidelines "call for the need to lower LDL cholesterol as much as possible to prevent cardiovascular disease."

He agreed, however, that high- or very-high-risk patients "have aggressive LDL targets that are often lower than what can be accomplished with high-dose, high-intensity statin monotherapy. Therefore, starting with combination therapy…will get more patients to goal more quickly, and will prevent more cardiovascular events."

Isaacs added: "It just makes sense that if you know a drug will not be strong enough, then you should start with two drugs."

He noted that this approach is commonly used for conditions such as diabetes and hypertension, "when monotherapy is not expected to achieve the desired results."

Isaacs also underlined that the combination of a statin plus ezetimibe "is appealing because of the price and ease of use."

Although PCSK9 inhibitors are more potent and achieve even lower LDL levels, "the higher price and need to take an injection has limited their use," he noted.

"One would expect that as the prices of PCSK9 inhibitors come down, their place in care pathways will move up since they are more effective and have proven cardiovascular benefit, but for now, statin plus ezetimibe is a potent and cost-effective way to achieve LDL targets in high- and very-high-risk patients," Isaacs concluded.

One issue Lloyd-Jones raised with the ESC/EAS guidelines is that they seem to have put a lot of weight Mendelian randomization analysis.

"Those are useful in understanding whether having low LDL-cholesterol levels or triglycerides naturally are better for you — of course they are — but they actually provide no evidence about treatment effects, and so I think what we need from that is actual data from the clinical trials to understand the treatment effects, both positive and negative."

He added that that "really then helps us to drive to how and in whom we want to achieve the lowest levels possible."

Lloyd-Jones said that Mendelian randomization analyses "continue to crop in a lot of these ESC and EAS documents," and although they are "elegant and interesting," they "don't really inform treatment at all."

No funding declared. Catapano declares relationships with Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Merck, Aegerion and Amgen.

European Atherosclerosis Society (EAS) 2021 Virtual Congress.

Atherosclerosis. 2021;325:99-109. Full text

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