The 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on cardiovascular disease prevention in clinical practice[1] continue to include risk-based low-density lipoprotein cholesterol (LDL-C) targets despite a change in US guidelines. Alberico L. Catapano, PhD, president of the EAS and a professor of pharmacology at the University of Milan, explains why to theheart.org | Medscape.
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theheart.org | Medscape: Despite the change in the US guidelines to move away from lipid targets, the 2016 ESC/EAS guidelines on cardiovascular disease prevention in clinical practice[1] include risk-based LDL-C goals for patients. Why did you choose that approach?
Dr Catapano: If you look at the ESC/EAS guidelines for the management of dyslipidemias from 2011[2] and the European guidelines on cardiovascular disease prevention[2] which were released a few months ago, we include LDL-C goals, but we also include the recommendation of a 50% reduction from baseline levels for higher-risk patients. Physicians requested an LDL-C target, but we have not excluded consideration of the intensity of therapy. By including it, we can take advantage of both approaches (Table).
Table. ESC/EAS Recommendations for Lipid Control
Risk CategoryLDL-C Goal Percentage ReductionVery high risk< 1.8 mmol/LAdapted from Piepoli MF, Hoes AW, Agewall S, et al.[2]
theheart.org | Medscape: An analysis from Israel, published in JAMA Internal Medicine,[3] showed support for a goal of < 100 mg/dL (2.6 mmol/L) but not < 70 mg/dL (1.8 mmol/L) in patients with established ischemic heart disease. What do you think of that paper?
Dr Catapano: This is an observational analysis, not a randomized controlled trial. All of the randomized trials show that the more you lower LDL-C, the greater the benefit, and that total mortality is decreased at longer follow-up. These investigators did not reliably assess the risk level of their population; it's not clear whether the patients who achieved LDL-C levels < 70 mg/dL level were higher-risk than those who reached higher levels (even if below 100 mg/dL). Finally, we do not know what level they started from, which is the most important consideration. It's possible that the group that got their LDL-C < 70 mg/dL started at a much lower baseline LDL-C level than those who reached 100 mg/dL.These data are confounded because you can't control for everything in an analysis like this. The study has value, but there is not sufficient evidence to draw the conclusion that "the data do not support treatment guidelines recommending < 70 mg/dL target LDL-C levels for patients with preexisting heart disease." We should trust the randomized controlled clinical trials.
theheart.org | Medscape: For risk assessment, are Europeans sticking with the EuroSCORE or are the pooled cohort equations ever used?
Dr Catapano: In the prevention guidelines, we recommend the SCORE but we have a whole section on risk assessment. The most important thing is to assess risk rather than which score you use. We are aware that the SCORE is not perfect and could be better. We suggest that each country use whatever validated local-risk estimation system is most relevant to their population. The SCORE is just an example of how you can calculate risk and apply that information to prevention. As long as people assess risk and use that to guide therapy, we are happy.
theheart.org | Medscape: Where do you see PCSK9 inhibitors fitting into preventive therapy?
Dr Catapano: There is no doubt that they are a huge step forward in clinical therapy. We have a lot of evidence showing that they lower LDL-C, but we still don't have evidence showing an effect on clinical events. Without that data, it's difficult to say where they fit in. Most probably they will be shown to lower events; preliminary studies suggest as much.[4,5] But we await the final answer from the randomized controlled trials.
First-line therapy for lipid lowering is statins, then ezetimibe. If you can't reach the goal with these, then you can consider adding a PCSK9 inhibitor.
theheart.org | Medscape: What about patients who are statin intolerant?
Dr Catapano: Statin intolerance is ill defined. The guidelines recommend using the maximally tolerated dose of statin, which takes intolerance into account, but we don't have a good clinical definition of intolerance. In those patients who cannot take a statin or who can't tolerate a high dose after having tried various doses or different statins or ezetimibe, you can consider a PCSK9 inhibitor.
theheart.org | Medscape: What do you think about the potential side effects of statins, particularly muscle symptoms and the risk for diabetes?
Dr Catapano: If you look at the randomized controlled trials, the reported muscle symptoms are almost negligible. In the real-world population, a lot of people complain about muscle symptoms but that doesn't mean 100% that it is a true side effect. Sometimes if you rechallenge them with another statin, they're fine. Clinicians should try to convince patients to try another statin or a different dose. That said, sometimes it's impossible to convince a patient to try again and/or that true effects exist; in those cases you could try ezetimibe or PCSK9 inhibitors.
In regard to diabetes, the duration of the trials[6] has not been long enough to definitively say that statins increase the cardiovascular risk associated with diabetes. It is not clear whether some of these people were already at higher risk for diabetes. Overall, the risk-benefit ratio for most patients favors statin therapy. I don't think there is much to worry about. We have to keep our eyes open, but the information so far is reassuring. Use if problems a new statin, or the lowest dose of statins and also use the strategy of a a statin every second day if still problems
theheart.org | Medscape: How do you respond to the so-called statin skeptics? First, let's discuss those who support statins for secondary prevention but are doubtful about the benefits in primary prevention.
Dr Catapano: The benefits of statins are proportional to the baseline risk of the patient. If you look at the meta-analysis from the Cholesterol Treatment Trialists (the Oxford group),[7] the benefits are seen in both the primary and secondary prevention populations. The relative risk reduction is about 22%; however, the absolute risk reduction is lower for primary versus secondary prevention, and the number needed to treat is higher. If you stratify by risk, there are some high-risk primary prevention patients who will benefit as much as secondary prevention patients.
theheart.org | Medscape: Others are concerned that physicians rely too much on drug therapy and forget about diet and lifestyle.
Dr Catapano: This is a major mistake. Lifestyle therapy comes first. Physicians should insist that patients make all efforts to improve their lifestyle even if they are on drug therapy.
theheart.org | Medscape: Then there are the more extreme skeptics who do not believe in the LDL-C–atherosclerosis hypothesis at all. How do you answer them?
Dr Catapano: First of all, it's not a hypothesis—it's a fact. I'm not sure how much more data you need to know that cholesterol carried within the LDL damages the arteries. There is a strong relationship between LDL-C and risk for cardiovascular disease. Of course, there are people who have heart disease without high cholesterol. You can be a smoker and never develop lung cancer.
theheart.org | Medscape: What would you like our audience to take away from this Q&A?
Dr Catapano: I would emphasize that they should measure and manage the LDL-C. If possible, look at the non-HDL-C, especially if the triglycerides are high (as addressed in several guidelines). The treatment strategy should take into account the patient's global risk. The higher the risk, the greater the benefit from lipid-lowering therapy.