ORIGINAL ARTICLE

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

Marc S. Sabatine, M.D., M.P.H., Robert P. Giugliano, M.D., Anthony C. Keech, M.D., Narimon Honarpour, M.D., Ph.D., Stephen D. Wiviott, M.D., Sabina A. Murphy, M.P.H., Julia F. Kuder, M.A., Huei Wang, Ph.D., Thomas Liu, Ph.D., Scott M. Wasserman, M.D., Peter S. Sever, Ph.D., F.R.C.P., and Terje R. Pedersen, M.D., for the FOURIER Steering Committee and Investigators*

March 17, 2017DOI: 10.1056/NEJMoa1615664

 Comments open through March 24, 2017

BACKGROUND

Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.

Full Text of Background...

METHODS

We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.

Full Text of Methods...

RESULTS

At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).

Full Text of Results...

CONCLUSIONS

In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633.)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991204/

The story of how PCSK9 was discovered.

This thing sounds too good to be real. I have a feeling that it will turn out to be somekind of fiasco once the practice gets wide spread for a certain length of time. Such thing has happened before many times.
LDL cholesterol must have certain duty or purpose for our body and mind for it to be present in our blood.
When the cholesterol level gets pushed too low, there has to be some undesirable effect that they (the naive-hungry researchers and the profit-driven biotech companies) failed (intentionally or accidentally) to notice in the studies.

In the papers, they never mentioned any bad effects of abnormally lower blood level of cholesterol.
For example, lower cholesterol is known to make people dumb and forgetful.
God created us in such way that we need certain amount of cholesterol in our blood.

They only paid attention to the lowering of cardiovascular morbidity and mortality.

"Safety

No significant between-group differences were seen in the overall rates of adverse events, serious adverse events, or adverse events thought to be related to the study agent and leading to discontinuation of the study regimen (Table 3TABLE 3Adverse Events and Laboratory Test Results.). Likewise, the rates of muscle-related events, cataract, neurocognitive adverse events, and hemorrhagic stroke did not differ significantly between the two groups. Injection-site reactions were rare, but they were more frequent with evolocumab (2.1% vs. 1.6%). The large majority of reactions (approximately 90% in each group) were classified as mild, and only 0.1% of the patients in each group stopped receiving the study agent because of an injection-site reaction. The rates of adjudicated cases of new-onset diabetes did not differ significantly between the two groups (hazard ratio, 1.05; 95% CI, 0.94 to 1.17). The rates of allergic reactions also did not differ significantly between the groups (3.1% vs. 2.9%). In the evolocumab group, new binding antibodies developed in 43 patients (0.3%), and development of neutralizing antibodies did not occur in any patient."( The above is from the article in full text which you have access by clicking the words highlighted)

Please note ".... no significant difference in neurocognitive adverse events, etc. ..."

In addition, in the second article quoted above in regard to how the PCSK9 was discovered, they mentioned

some families where the genes producing PCSK9 are missing and LDL levels are congenitally low around 20 or 30,

and atherosclerotic disease is very rare, and everything else including brain function is normal, further indicating

the fact that the extremely low LDL does not affect neurocognitive function.

The question regarding what the lowest ideal LDL level is has been around in Cardiology community

for a long time.

Certainlly the lowest LDL level statins could bring down has not affected neurocognitive function statistically

in all the numerous double blind studies.

One of the commonly accepted recommended lowest LDL level was that of cord blood

of the newborn, which is between 40 and 50. 

I understand what you are saying, however, WM.

What you said has been in the minds of these researchers as well as all the cardiologists

for a long time.

So far this study says that the lower the LDL is, the better.

They have not found the lower limit of the LDL below which is dangerous.