High CRP Linked to Bigger Absolute Drops in CV Events for Patients Taking Evolocumab

ORLANDO, FL—Patients with atherosclerotic cardiovascular disease treated with the PCSK9 inhibitor evolocumab (Repatha; Amgen) have a consistent reduction in the risk of cardiovascular events regardless of baseline high-sensitivity C-reactive protein (hsCRP) levels, according to a new analysis of the FOURIER trial.

“We found that the relative benefit of evolocumab was consistent across the range of hsCRP, with an approximate 20% reduction in major adverse CV events compared to placebo,” lead investigator Erin Bohula, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “However, patients with high hsCRP are at higher risk of future CV events. For that reason, they tended to get a greater absolute benefit, meaning that in those patients with higher hsCRP, the number needed to treat is lower. In patients with the highest hsCRP, the absolute risk reduction was 3%, translating to a [number needed to treat] of 33 at 3 years.”

Comparatively, in the overall trial, the number needed to treat to prevent one major adverse cardiovascular event—the study’s secondary endpoint that included only cardiovascular death, MI, or stroke—was 50 over 3 years.

The findings have “cost implications, as these are the patients where a provider is most likely to be able to prevent a major CV event, and in a cost-constrained setting, where the most aggressive secondary preventative strategies could be employed,” said Bohula.

The results of the study were presented last week at the American College of Cardiology 2018 Scientific Session and published simultaneously in Circulation.

High LDL Cholesterol, Mix of hsCRP Levels

In FOURIER, a 27,564-patient clinical outcomes study, adding evolocumab to statin therapy reduced the relative risk of the study’s primary endpoint—a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization—by 15% when compared with placebo. The secondary endpoint was reduced by 20%.

The aim of the present study was to determine whether hsCRP levels could define patients who might experience more or less benefit, said Bohula, as well to understand what might be driving residual risk in patients with well-controlled LDL cholesterol levels.

Overall, 7,981 patients had a low baseline hsCRP (< 1.0 mg/L), 11,177 had intermediate hsCRP (1.0-3.0 mg/L), and 8,337 had high hsCRP (> 3.0 mg/L). Patients with high hsCRP were more likely to have other cardiovascular risk factors, such as hypertension, diabetes, and renal dysfunction, and they were more likely to smoke. They were also more likely to have comorbid conditions such as stroke and peripheral artery disease.     

In the three hsCRP groups, treatment with evolocumab reduced the relative risk of the primary endpoint by 18%, 7%, and 20%, respectively (P = 0.17 for interaction). The relative reduction in the risk of the secondary endpoint was 19%, 13%, and 27%, respectively (P = 0.26 for interaction).

Among patients with hsCRP levels 3.0 mg/L or greater, the absolute risk of the primary endpoint was reduced by 2.7% compared with the 1.6% absolute risk reduction seen in patients with hsCRP less than 1.0 mg/dL. Similarly, for those with elevated hsCRP, the absolute reduction in the risk of the study’s secondary endpoint was 3.0% versus 0.8% among those with hsCRP less than 1.0 mg/L.

Dual Axis for Treatment

To TCTMD, Bohula said FOURIER, which tested evolocumab for LDL cholesterol-lowering, and CANTOS, which tested canakinumab (Novartis), a fully human monoclonal antibody that targets inflammatory pathways, are complementary for the secondary prevention of cardiovascular events.

Our data would suggest that the inflammatory axis could be another therapeutic target even in patients with extremely well-controlled lipids. Erin Bohula

“Therapies we have studied in the past, such as statins and ezetimibe, reduced both LDL cholesterol and hsCRP, making it hard to determine whether the benefit was primarily driven by reductions in LDL cholesterol, hsCRP, or both,” she said. “Canakinumab is an anti-inflammatory that does not alter LDL cholesterol levels. Evolocumab, and the other PCSK9 inhibitor, reduce LDL cholesterol but do not alter hsCRP. Both demonstrated CV benefit, supporting the hypothesis that both are maybe important targets for secondary prevention.”

One question the researchers grappled with, however, was whether inflammation remains an important target in the setting of aggressive/potent lipid-lowering therapy, such as when LDL cholesterol levels are less than 82 mg/dL as they were in CANTOS. “In our analysis, we found that hsCRP did appear to be associated with CV risk even when LDL cholesterol was extremely low,” said Bohula. “So, our data would suggest that the inflammatory axis could be another therapeutic target even in patients with extremely well-controlled lipids.”

In the study, among patients who had an on-treatment LDL of less than 20 mg/dL, the adjusted 3-year primary event rate among those with low, intermediate, and high hsCRP levels was 9.0%, 10.8%, and 13.1%, respectively. The adjusted 3-year secondary event rates were 5.3%, 6.7%, and 8.9%, respectively.

In December 2016, the US Food and Drug Administration (FDA) permitted new labelling claims for evolocumab, making it the first PCSK9 inhibitor to be indicated for the prevention of cardiovascular events. The ODYSSEY trial recently showcased a significant reduction in the risk of major cardiovascular events, including all-cause mortality, in patients with a recent ACS treated with alirocumab (Praluent; Regeneron/Sanofi), the second PCSK9 inhibitor. At present, though, alirocumab is only indicated for LDL-lowering, although the company is likely to ask the FDA for a cardiovascular event-reduction claim.