Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy

Circulation. 2018 Jul 10;138(2):141-149. doi: 10.1161/CIRCULATIONAHA.118.034645. Epub 2018 May 1.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / therapeutic use*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / therapeutic use*
  • Biomarkers / blood
  • C-Reactive Protein / metabolism*
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control*
  • Cholesterol, LDL / blood*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Dyslipidemias / blood
  • Dyslipidemias / complications
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / enzymology
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Inflammation / blood
  • Inflammation / complications
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Male
  • Middle Aged
  • PCSK9 Inhibitors*
  • Proprotein Convertase 9 / metabolism
  • Risk Assessment
  • Risk Factors
  • Serine Proteinase Inhibitors / adverse effects
  • Serine Proteinase Inhibitors / therapeutic use*
  • Time Factors
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal, Humanized
  • Anticholesteremic Agents
  • Biomarkers
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • PCSK9 Inhibitors
  • Serine Proteinase Inhibitors
  • bococizumab
  • C-Reactive Protein
  • PCSK9 protein, human
  • Proprotein Convertase 9

Associated data

  • ClinicalTrials.gov/NCT01975376
  • ClinicalTrials.gov/NCT01975389