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Published on: August 28, 2018
Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy
Aruna D Pradhan1,2, Aaron W Aday2,3, Lynda M Rose2
1Department of Medicine, Division of Cardiovascular Medicine, VA Boston Healthcare System, West Roxbury Campus, MA (A.D.P.). apradhan@bwh.harvard.edu.
Insights
Statin and PCSK9 inhibitor therapy significantly lowers LDL cholesterol but residual inflammatory risk, indicated by hsCRP levels, persists. Higher on-treatment hsCRP levels were associated with increased cardiovascular event rates in patients receiving both therapies.
Area of Science:
- Cardiology
- Pharmacology
- Inflammation Research
Background:
- Statin therapy combined with PCSK9 inhibition effectively reduces LDL cholesterol and cardiovascular events.
- The role of residual inflammatory risk, measured by on-treatment high-sensitivity C-reactive protein (hsCRP), in patients on combined therapy is not well-defined.
Purpose of the Study:
- To evaluate residual inflammatory risk in patients receiving both statin therapy and bococizumab, a PCSK9 inhibitor.
- To assess the association between on-treatment hsCRP levels and cardiovascular event rates in this patient population.
Main Methods:
- A post hoc analysis of 9738 patients from the SPIRE-1 and SPIRE-2 trials was conducted.
- Patients received statin therapy plus bococizumab, with on-treatment hsCRP (hsCRPOT) and LDL-C (LDL-COT) measured at 14 weeks.
- Cardiovascular events (myocardial infarction, stroke, unstable angina, cardiovascular death) were tracked.
Main Results:
- Bococizumab significantly reduced LDL-C by -60.5% at 14 weeks, while hsCRP showed minimal change.
- Patients with higher hsCRPOT levels (>3 mg/L) had a significantly increased risk of cardiovascular events (HR 1.62) compared to those with hsCRPOT <1 mg/L.
- No significant interaction was observed between hsCRPOT levels and the relative risk reduction achieved with bococizumab.
Conclusions:
- Residual inflammatory risk, indicated by elevated on-treatment hsCRP, persists in patients treated with statins and PCSK9 inhibition.
- Higher hsCRPOT levels are associated with a greater risk of cardiovascular events, even with intensive LDL-C lowering.
- These findings suggest that inflammatory pathways may contribute to cardiovascular risk independently of LDL-C levels in patients on combined therapy.
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.
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