The FOURIER Trial – Are We Entering a New Era in Cardiovascular Medicine?

The results of the recently completed FOURIER trial suggest that we have taken a huge step forward in the pharmacological therapy atherosclerotic cardiovascular disease (ASCVD).

On February 2, 2017 the biotechnological company Amgen announced that the FOURIER trial evaluating whether the drug evolocumab (Repatha) reduces the risk of cardiovascular events in patients with clinically evident ASCVD met its primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary composite end-point (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke).

According to Amgen’s press release, “no new safety issues were observed.”

FOURIER - Are We Entering a New Era in Cardiovascular Medicine?

FOURIER included 27.500 patients with either a history of stroke, myocardial infarction or peripheral artery disease and an LDL cholesterol (LDL-C) >70 mg/dL (1.8 mmol/L) or non-HDL cholesterol (non-HDL-C) > 100 mg/dl despite optimized statin therapy. Patients were randomized to received Repatha administered by subcutaneous injections, 140 mg every two weeks or 420 mg monthly or identical placebo.

In other words, treatment with Repatha on top of optimized statin treatment in patients with ASCVD appears to be clinically useful. At this moment, no further results are available. We do not know the magnitude of the risk reduction nor the number of patients needed to treat (NNT) to prevent an event.

A couple of months ago we saw the results of the GLAGOV trial showing that treatment with Repatha reduces atherosclerotic plaque volume in patients with coronary artery disease (1).

How Does Evolocumab (Repatha) Work?

Evolocumab reduces blood levels of LDL-C by approximately 60%. It has several other modifying effects on blood lipids, including reductions of 52.0% in non-HDL-C, 47.3% in apolipoprotein B (ApoB), 36.1% in total cholesterol, 12.6% in triglycerides, and 25.5% in lipoprotein(a) (2).

Reduction in LDL-C levels with statin treatment in patients with ASCVD has proved to be effective in reducing rates of major cardiovascular events in numerous large outcome trials. However, limited information is available on the clinical efficacy of lowering LDL-C further than can be achieved by statin treatment. One study, using ezetimibe suggested that such treatment may reduce the risk of cardiovascular events (3).

The liver is responsible for the production and clearance of low-density lipoprotein (LDL). Liver cells express specific receptors on their surface that bind LDL and remove it from the bloodstream. After binding to the LDL-receptor, the LDL/LDL-receptor complex is taken up by endosomes within the cells. The LDL-receptor then moves back to the cell surface where it can bind to additional LDL-particles. The process leads to removal of LDL-particles from the circulation and lower LDL-cholesterol levels. The free LDL left within the cells is transported to lysosomes and degraded into lipids, free fatty acids, and amino acids.

PCSK9 (Proprotein convertase subtilisin-like/kexin type 9) is a protein that regulates the expression of LDL-receptors in the liver.

PCSK9 is produced by the liver. It binds to the LDL-receptor on the surface of liver cells, together with LDL. It also moves into the cell, together with the LDL-receptor/LDL complex and prevents the recycling of the LDL-receptor to the cell surface. Thus, PCSK9 is responsible for the degradation of LDL-receptors and therefore plays a critical role in the regulation of LDL-cholesterol levels.

Genetic mutations that lead to a loss of PCSK9 function are found in 1–3 percent of the population. These mutations are associated with very low LDL-C and a low risk of ASCVD.

Evolocumab (Repatha) is a monoclonal antibody directed against PCSK9. It lowers LDL-C by blocking the interaction of PCSK9 with the LDL-receptor on the surface of liver cells. This allows LDL-receptors to recycle to the cell surface, after releasing LDL within the cell, instead of being taken up and degraded in lysosomes. Increased concentration of LDL receptors on the surface of liver cells improves clearance of LDL, which is reflected in lower levels of LDL-C.


Concerns have emerged about a possible association of neurocognitive impairment with PCSK9 inhibitor therapy.

The brain houses an estimated 25 % of the body’s total cholesterol (4). Cholesterol plays a role in cellular signaling within the brain. Hence, in theory, all lipid-lowering therapies may impair neurocognitive function. According to one survey, memory complaints are the second most common adverse effect reported by patients on statin medications (5).

In 2012, the US Food and Drug Administration (FDA) mandated a black box warning change for all statin drugs citing “ill-defined memory loss or impairment” (5). In early 2014, the FDA directed developers of PCSK9 inhibitors to monitor neurocognitive adverse effects and consider neurocognitive testing in at least a subset of participants in ongoing late-stage trials

A subset consisting of about 1900 patients in FOURIER also participated in the EBBINGHAUS trial which tested cognitive function in patients randomized to evolocumab or placebo. According to the Amgen’s press release, evolocumab was non-inferior to placebo for the effect on cognitive function. In other words, cognitive dysfunction was not more common in patients treated with evolocumab compared with placebo.

The Unanswered Questions

The FOURIER and EBBINGHAUS trials will be presented at the forthcoming 66th Annual Scientific Session of the American College of Cardiology in Washington DC, March 17 and 18, 2018. Although Amgen’s press release may excite current and potential shareholders, prudence is required on behalf of the practicing clinician, until the primary trial data become available.

The results of the FOURIER and GLAGOV trials strongly suggest that aggressively lowering the availability of atherogenic lipoproteins such as LDL, VLDL, and lipoprotein(a) will be translated into less atherosclerosis and lower risk of future cardiovascular events. The studies provide strong support for the hypothesis that lipoproteins carrying ApoB play an important role in the pathogenesis of ASCVD (6).

The FOURIER data clearly strengthen the role of LDL-C as a treatment target. It provides support for “the more, the better” hypothesis when it comes to the question of how much lowering of LDL-C is beneficial.

No “new safety issues” were observed with evolocumab in the FOURIER trial. What this exactly means is hard to tell. However, it clearly suggests that there were no severe or unexpected side effects associated with the drug compared with placebo. This is further supported by the results of the EBBINGHAUS trial suggesting that evolocumab does not cause neurocognitive dysfunction.

FOURIER started including patients in February 2013 and was completed in November 2016. Hence, we may assume that the mean follow-up period was approximately three years.

Previous experience with statin drugs suggests that adverse effects are more common in “real life” than reported by the placebo-controlled randomized clinical trials. One explanation for this phenomenon is that side-effects may occur late, even after many years of treatment, and would therefore not be detected in a clinical trial that is run for 3-5 years.

Hence, although EBBINGHAUS will calm many of those who believe that aggressive lowering of LDL-C may adversely affect brain function, it will be hard to exclude the possibility that such harm may take more than three years, maybe even 5-10, to develop.

Finally, as we don’t yet know the magnitude of the treatment effect in the FOURIER trial, the true treatment value (efficacy combined with costs) can not be addressed. Currently the annual cost is about $14,100 for the two PCSK9 inhibitors, evolocumab and alirocumab respectively. Hence, at the current price, widespread use of these drugs will lead to enormous costs.

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