FOURIER: How Low Should LDL Go?

Arefa Cassoobhoy, MD, MPH; Melissa Walton-Shirley, MD


April 14, 2017

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Arefa Cassoobhoy, MD, MPH: Hi, everyone. My name is Arefa Cassoobhoy. We are here at Medscape to discuss the recent American College of Cardiology (ACC) 2017 Scientific Sessions and the key studies with implications for those of us practicing in primary care. Dr Melissa Walton-Shirley is here today and she is a contributor to Medscape.

I am excited to talk to you today about the ACC conference. The hot trial was FOURIER.[1] Could you give us some background on that?

Evolocumab and LDL Lowering: FOURIER

Melissa Walton-Shirley, MD: The molecule evolocumab was studied for the target of low-density lipoprotein cholesterol (LDL-C) lowering. We had a cohort of 27,000 patients with stable vascular disease and a history of myocardial infarction (MI), stroke, or symptomatic peripheral arterial disease (PAD). The patients were on a statin, either high-intensity or moderate-intensity, with or without ezetimibe.

Patients were injected with either evolocumab 140 mg every other week or 420 mg monthly. The results were astounding, with LDL-C lowering of 59%; 42% of patients had an LDL-C < 25 mg/dL. One of the trialists remarked that this was "at a newborn level." We have not seen LDLs like this before in any trial.

This was an interesting trial because it was actually powered for the secondary endpoint that included MI, stroke, and cardiovascular (CV) death, and it reduced those outcomes by 20%. This was a versus-placebo arm and these were mostly males, mean age 63 years.

Dr Cassoobhoy: Could you explain to me why the secondary endpoints included CV mortality but the primary endpoint did not? When I was reading the article, that was a little confusing.

Dr Walton-Shirley: Yes, the primary endpoint was a composite of MI, CV death, revascularization, and unstable angina. It was fairly watered down, but patients receiving evolocumab met that primary endpoint as well with a 15% reduction.

But the conversation has been about this lack of mortality reduction. With a number needed to treat of 74, we are going to have to spend about $1 million to try to reduce one event—although that is just an on-the-surface, mile-high look. There is going to be a calculation in about a year of cost-effectiveness. They will have to include the improvement in heart attack, cost of prevention, stroke prevention, nursing home stay, etc. It will all have to go in for cost-effectiveness analysis.

Dr Cassoobhoy: There will be an arm that follows 6000 people in an open-label extension study. When we are doing these long-term follow-up studies, what do you think the long-term impact is going to be of this crazy-low LDL? There were levels as low as 30 mg/dL, and even lower—down to 19 mg/dL. There was a side-arm study evaluating brain function as well.

Dr Walton-Shirley: That's right. There were no cognitive deficits. Remember that this was a median 22-month follow-up. We are still in that phase. Honestly, I think we reported on this molecule too soon for a definitive evaluation of mortality benefit. It was reassuring that we did not see diabetes, cognitive dysfunction, or an increased signal for cancer.

At this point, what we know about this molecule and the sum total of all the trials with this molecule is that it is safe. The only side effect we really saw was stinging at the injection site, but that was not enough to make the patients stop using the drug. Patients were compliant with the drug.

Applying FOURIER to Familial Hypercholesterolemia

Dr Walton-Shirley: We know that patients with familial hypercholesterolemia (FH) are likely to get sick at a very young age. I think it is safe to go ahead and start this drug in those patients. We did see that, over this follow-up period to date, mortality curves of users and nonusers are diverging. I think that if we use the same trajectory, we will probably eventually get a mortality reduction.

Dr Cassoobhoy: As a PCP with a patient with FH, should I be more aggressive about screening patients for this condition? Should I be referring them to the cardiologist earlier? How should I change my management based on this study?

Dr Walton-Shirley: I posed this question to Dr Christie Ballantyne, director of the Center for Cardiovascular Disease Prevention at Methodist DeBakey Heart Center in Houston and one of the world's leading lipidologists. He suggested testing for FH in patients with an LDL ≥ 190 mg/dL. I contacted the lab where I do a lot of my genetic testing. Right now there is an out-of-pocket cost of about $1500 for the complete genetic test, although there is a shorter version of the test that we could get for $300-$400 dollars. For some, that is still cost-prohibitive.

Dr Cassoobhoy: That could be a huge number of patients.

Role for Statin-Intolerant Patients?

Dr Cassoobhoy: What about the patients who do not necessarily have a condition like FH but are statin intolerant? This study was conducted in patients on statins. How does it apply to the statin-intolerant population?

Dr Walton-Shirley: That is a very good question, and I have a feeling that we are going to find out in the next 5-10 years whether you really even need a statin anymore. We cannot extrapolate this to the entire statin-intolerant population because they were not studied in this trial.

I have, however, already extrapolated it to one of my patients who is statin-intolerant and has continued to progress and have events. I was able to get that patient approved for this therapy by his insurance provide, but only after I was denied three or four times. It took a lot of work on behalf of myself and my office staff to try to get it approved.

Dr Cassoobhoy: What advice do you have for PCPs out there trying to get this drug approved?

Dr Walton-Shirley: Let me tell you: I know it sounds terrible, but I would offload that work to a good lipid clinic somewhere.

FOURIER vs Guidelines

Dr Cassoobhoy: Before we finish up, I want to ask you how you think results from this trial might influence how we look at the 2013 American College of Cardiology/American Heart Association lipid guidelines.[2] Those guidelines did not really focus on pushing that LDL down so low. Should we now be doing that or looking at a percent reduction in LDL?

Dr Walton-Shirley: There was a really good article[3] in the June 2004 issue of the Journal of the American College of Cardiology that said the optimal LDL is 50-70 mg/dL, because that is the hunter-gatherer LDL. In America at that point in time, the average person's total cholesterol was 208 mg/dL and LDLs were 130 mg/dL Half of us had atheroma by age 50 years. We do not think that average is optimal. Based on that information alone, we probably should be pushing our LDLs lower.

Dr Cassoobhoy: Thank you so much for talking to us about this trial. This is valuable information for our audience. We need to fight the good fight if our patients need this medication. But we will have to see how it all pans out in terms of cost versus success with the drug.


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