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BARCELONA -- Forget 70 mg/dL as an LDL target, and 50 mg/dL is "dated" -- for high-risk patients, pull out all the stops and aim for <20 mg/dL.

That recommendation, which runs far ahead of any treatment guidelines, emerged from a prespecified subset analysis from the FOURIER trial, which found that aggressive LDL reduction with the PCSK9 inhibitor evolocumab (Repatha) reduced the risk of MI by 15% compared with placebo, which meant that treating 74 patients for 2.2 years would reduce one event.

But the question remained: how low could one go and still be safe? In this new analysis, Robert Giugliano, MD, of Brigham and Women's Hospital in Boston and colleagues investigated outcomes among patients who achieved extremely low LDL-cholesterol levels. The results of that analysis led Giugliano to conclude that LDL-cholesterol levels of less than 20 mg/dL are safe for high-risk patients.

The findings were reported at the (ESC) meeting and simultaneously published in the Lancet.

"I think what we need to do is, [at] my hospital and other hospitals, to stop sending warnings when we get LDL less than 40," Giugliano told 番茄社区app.

FOURIER enrolled 27,562 high-risk patients and, in this analysis, the researchers investigated the relationship with LDL-cholesterol at 4 weeks into the study, as well as outcomes at 2.2 years of follow-up. Patients who failed to have 4-week measurements, or who reached a primary endpoint or safety endpoint, before the 4-week mark, were excluded from the analysis.

In addition to looking at FOURIER composite endpoint of cardiovascular death, MI, and stroke, they drilled down to investigate 10 key, prespecified safety endpoints:

• Serious adverse events
• Adverse events leading to study drug discontinuation
• Elevation in hepatic transaminase concentration of more than three times above normal
• New or recurrent cancer
• Cataract-related adverse events
• Elevation in creatine kinase concentration of more than five times above normal
• Hemorrhagic stroke
• Neuro-cognitive adverse events
• New-onset diabetes mellitus
• Non-cardiovascular death

Cognitive decline is a concern often raised in conjunction with aggressive LDL lowering, but Giugliano said there was no evidence to support that suspicion.

"Ten percent of 25 982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L [9.00 mg/dL], 8003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2/6 mmol/L, and 4395 (17%) patients achieved concentrations of 2.6 mmol/L or higher," Giugliano's group wrote. "There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L, P=0.0012) for the primary endpoint ... Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events."

During an ESC press briefing, moderator Ian Maklim Graham, MD, of Wicklow, Ireland who served on the ESC's cholesterol guideline committee noted that the "low, low" target option was the subject of some controversy when the ESC updated guidelines in 2016. Those guidelines suggest a target of 50 mg/dL, "which was controversial at the time but now seems dated."

But ESC spokesperson Joep Perk, MD, editor of the European Journal of Preventive Cardiology, raised a practical concern: "now we say 50 mg/dL and we can't get to that goal; can we afford to get to 20 mg/dL?"

The question of affordability is not insignificant since the cost of evolocumab and other PCSK9 inhibitors has proven to be a major barrier to use. With a list price of $14,400 per patient per year, third-party payers have been reluctant to approve coverage. That reluctance prompted drug developer Amgen offer to refund insurers the cost of the drug if an eligible patient had a heart attack on treatment.

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