Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy

Abstract

Background: The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain.

Methods: We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death.

Results: At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was -60.5% (95% confidence interval [CI], -61.2 to -59.8; P<0.001; median change, -65.4%) as compared to 6.6% (95% CI, -1.0 to 14.1; P=0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRPOT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81-1.66), and 1.62 (95% CI, 1.14-2.30) (P-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT. Comparable adjusted hazard ratios for LDL-COT (<30, 30-50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (P-trend=0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (P-interaction=0.87).

Conclusions: In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01975376, NCT01975389.

Keywords: LDL-C; PCSK9; PCSK9 inhibitor; hsCRP; inflammation; residual risk.

© 2018 American Heart Association, Inc.

Figures

Figure 1.. Mean percent change in lipid levels from baseline to 14 weeks according to hsCRPOT.

Median on-treatment lipid values in each hsCRPOT group are shown to the right of each plot.

Figure 2.. Relationship between hsCRPOT on a continuous scale and the adjusted event rate for the trial primary endpoint (myocardial infarction, stroke, unstable angina requiring urgent coronary revascularization, and cardiovascular death).

Model adjusts for age, sex, current smoking, diabetes, hypertension, and body-mass index) statin intensity at enrollment (moderate-intensity or high-intensity), and LDL-COT. Dots represent individual hsCRPOT values. The solid red line indicates the estimated event curve from adjusted models.

Figure 3.. Risk association of hsCRPOT and LDL-COT with incident cardiovascular events according to categories of each biomarker.

Adjusted for age, sex, current smoking, diabetes, hypertension, and body-mass index) statin intensity at enrollment (moderate-intensity or high-intensity), and hsCRPOT and LDL-COT as appropriate. Models for hsCRPOT are on the left and models for LDL-COT is on the right.