PCSK9 inhibitors confer greater benefit in elevated baseline LDL

Jennifer G. Robinson

SANTA ANA PUEBLO, N.M. — Patients with elevated LDL at baseline appear to have the most relative risk reduction when treated with PCSK9 inhibitors, according to a presentation at American Society for Preventive Cardiology Congress on CVD.

“[FOURIER and ODYSSEY Outcomes] have come out, and they’ve really fallen short of those expectations of 50% relative risk reductions, with relative risk reductions more like 15% to 20%,” Jennifer G. Robinson, MD, MPH, professor in the departments of epidemiology and medicine and director of the Prevention Intervention Center at University of Iowa in Iowa City, said in the presentation. “We need to give some consideration to why that is.”

At 2 years, patients in the FOURIER trial assigned evolocumab (Repatha, Amgen) had a 25% relative risk reduction compared with those assigned placebo.

“I don’t think it’s going to be more than 25% if the trial went on for 10 years because this is what we have seen in the [Cholesterol Treatment Trialists] analysis of the statin trials,” Robinson said.

For the high- vs. moderate-intensity statin trials, the majority of the relative risk reduction emerged in the first year and remained the same throughout subsequent years, she said.

The reason the PCSK9 inhibitor trials may have been short of expected relative risk reductions may have been due to baseline LDL levels, according to the presentation. Patients in the ODYSSEY Outcomes trial had a mean baseline LDL of 87 mg/dL and those assigned alirocumab (Praluent, Sanofi/Regeneron) had a relative risk reduction of 15% in major CV events at a median of 2.8 years. Patients in the FOURIER trial, with a baseline LDL of 92 mg/dL, had a relative risk reduction in major CV events of 15% in a median of 2.2 years if assigned evolocumab. Yet the patients in the SPIRE-2 trial of bococizumab (Pfizer) had a higher baseline LDL of 134 mg/dL and achieved a relative risk reduction of major CV events of 21% after a median of 1 year.

Notably, in the ODYSSEY Outcomes trial, patients with a baseline LDL over 100 mg/dL had the most improvement in outcomes with alirocumab, and there was no effect in patients with lower LDL levels at baseline.

As Cardiology Today previously reported in April, in a meta-analysis of all the trials on ezetimibe, statin and PCSK9 inhibitors published in JAMA, Robinson and colleagues assessed baseline LDL and found that when LDL is greater than 160 mg/dL, there was a 28% relative risk reduction in mortality. Each 1-mmol/L decrease was also associated with a 14% additional reduction in CV mortality.

“Baseline LDL matters, and appears to be driven by the reduction in cardiovascular mortality,” Robinson said.

A baseline LDL of about 100 mg/dL is a critical number regarding the largest absolute CVD risk reduction benefit. This may be because greater coronary atherosclerosis regression occurs when LDL levels are less than 100 mg/dL for both high-intensity statins and statin with or without evolocumab.

“There’s been a change in the pathophysiology with acute coronary syndromes in statin-treated patients, where plaque erosion is increasingly the cause rather than plaque rupture,” Robinson said.

Calculating net benefit allows clinicians to compare different patients with different levels of CV risk and LDL levels on maximal statin therapy. Net benefit can inform cost effectiveness, according to the presentation. All patients with CVD or familial hypercholesterolemia should be on statin therapy. Patients who might be considered for the addition of a non-statin includes those who are at extremely high risk and very high risk, both of which include CVD and other conditions such as diabetes, polyvascular disease or recurrent CVD events.

The cost effectiveness may influence whether the payer will cover the cost of a PCSK9 inhibitor, according to the presentation. A number between 21 and 28 may be within a realm of cost effectiveness when PCSK9 monoclonal antibodies are discounted, especially in patients with high or very high risk or when LDL levels are high, Robinson said.

“Targeting those who have CVD and FH, diabetes or extensive or active vascular disease makes sense with LDLs over 70 [mg/dL], but for those very high-risk people with less extensive vascular disease or better controlled risk factors, LDLs over 100 [mg/dL] is a good number,” Robinson said. “For the high-risk people such as those with well-controlled risk factors and more limited cardiovascular disease or primary prevention familial hypercholesterolemia, LDLs over 130 [mg/dL] would always be the right answer. If you want one number, I’d say an LDL over 100 [mg/dL] seems to be the magic number to get the maximum benefit from therapy, although there are selected patients below that that might benefit if they have extremely high risk and a poorly controlled metabolic milieu.” – by Darlene Dobkowski

Reference:

Robinson JG. PCSK9 inhibitors: When, how and in whom. Presented at: American Society for Preventive Cardiology Congress on CVD; July 27-29, 2018; Santa Ana Pueblo, New Mexico.

Disclosure: Robinson reports she received research grants to her institution from Acasti, Amarin, Amgen, AstraZeneca, Eisai, Esperion, Merck, Pfizer, Regeneron, Sanofi and Takeda and consulted for Amgen, Merck, Pfizer, Regeneron and Sanofi.