PCSK9 inhibitors may slow progression of aortic stenosis

Evolocumab (Repatha) decreases LDL cholesterol and has significant impact on Myocardial infarction type and size. Researchers in an additional analysis of the FOURIER trial have found that PCSK9 inhibitors may slow the progression of aortic stenosis and reduce need for aortic valve replacement. The new research has been published in JAMA Cardiology.

The researchers conducted analysis to evaluate association between lipoprotein(a) and low-density lipoprotein–cholesterol concentrations and aortic stenosis events, and find whether proprotein convertase subtilisin/kexin type 9 inhibition reduce the risk of aortic stenosis events or not.

Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS.

The results of the post hoc exploratory analysis has indicated that higher lipoprotein(a) (Lp[a]) was associated with a higher risk of subsequent aortic valve replacement.This suggests that specific long-term lipid-lowering therapy could prevent or slow the progression of aortic stenosis.

The post hoc analysis was performed between September 2019 and February 2020, which is nearly 4 years after the completion of the multinational, phase 3 FOURIER trial.

For the purpose of the analysis, investigators defined aortic stenosis events as new or worsening aortic stenosis reported by trial sites or an aortic valve replacement.

Investigators used multivariable hazards model to evaluate the adjusted risk of aortic stenosis events.

In this secondary analysis of 63 patients from the FOURIER trial elevated lipoprotein(a) concentrations were associated with higher rates of aortic stenosis events, including aortic valve replacement.

Analyses were adjusted for multiple factors including Lp(a) and LDL-C corrected for Lp(a) content, age, diabetes, hypertension, smoking state, and eGFR.

Upon analysis, investigators identified aortic stenosis events in 63 patients from the FOURIER trial. Of these, 26 were aortic valve replacements and the remaining were site-reported aortic stenosis events without valve replacement. Of the 26 instances of aortic valve replacements, 18 were surgical, 7 were trans catheter, and 1 was of unspecified type.

Results of the analysis indicated elevated Lp(a) concentrations were significantly associated with aortic valve replacement . The results also suggested elevated Lp(a) concentrations were associated with increased rates of aortic stenosis events .

Furthermore, corrected LDL-C concentration did not appear to be significantly associated with aortic stenosis events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P=.14). The overall hazard ratio for aortic stenosis events with evolocumab was 0.66 ,with no apparent association in the first year (hazard ratio, 1.09 [95% CI, 0.48-2.47]) but a hazard ratio of 0.48 (95% CI, 0.25-0.93) after the first year of treatment.

The researchers concluded that higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial.

"We have identified a possible beneficial outcome of PCSK9 inhibition on the risk of AS events, raising the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS," authors wrote. "These exploratory findings merit further investigation with a dedicated randomized clinical trial."

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This study, "An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial," was published JAMA Cardiology.