hsCRP levels at and after ACS associated with risk of recurrent MACE and death
Association of Initial and Serial C-Reactive Protein Levels With Adverse Cardiovascular Events and Death After Acute Coronary Syndrome - A Secondary Analysis of the VISTA-16 Trial
Introduction and methods
Efforts are made to identify biomarkers associated with the residual risk of ischemic events or death that is observed following an acute coronary syndrome (ACS), despite optimal guideline-directed coronary revascularization and antiplatelet and LDL-c lowering therapy. C-reactive protein (CRP) is an inflammatory biomarker that is independently associated with future CV events, irrespective of LDL-c level [1,2]. High-sensitivity (hsCRP) has better predictive value than traditionally measured CRP .
Targeted anti-inflammatory therapy is beneficial in patients with chronic atherosclerotic CV disease and elevated hsCRP levels, and patients in whom the hsCRP level decreases in response to this treatment have a better prognosis than those in whom the hsCRP level remains high .
Increasing hsCRP levels measured early after ACS are associated with short-term adverse outcomes , irrespective of troponin levels . It is, however, unclear whether the subsequent temporal change in hsCRP level provides further prognostic information.
This study therefore assessed baseline and serial hsCRP levels for 16 weeks (at week 1, 2, 4, 8 and 16) in optimally treated patients with ACS. This is a secondary analysis of the Vascular Inflammation Suppression to Treat Acute Coronary Syndromes for 16 Weeks (VISTA-16) trial, a double-blind, randomized, multicenter trial of the secretory phospholipase A2 inhibitor varespladib in 5145 patients. Patients with LDL-c level not at goal according to local guidelines despite maximal statin therapy were excluded. The primary end point was a major adverse cardiac event (MACE), which was the composite of CV death, nonfatal myocardial infarction (MI), stroke, or hospitalization for unstable angina at 16 weeks. The VISTA-16 study was terminated early due to futility and possible harm in the varespladib group. The counting process method was applied to account for hsCRP being a time-dependent repeated measures covariate, and dynamic changes in the hsCRP trajectory of a patient were identified for a series of time intervals . 4257 Patients were included in this analysis.
- In the total study population, median baseline hsCRP was 10.5 mg/L (IQR: 4.2-30.3 mg/L, to convert to nm/L, multiply by 9.524). The varespladib group showed a mean hsCRP change of -20.73 mg/L (95%CI: -22.5 to -19.22 mg/L) and the placebo group of -19.72 mg/L (95%CI: -21.22 to -18.22)(P=0.35).
- In multivariable Cox proportional hazards regression models, baseline levels were independently associated with MACE (HR: 1.36 per SD change, 95%CI: 1.13-1.63), after adjustment for drug treatment. Baseline hsCRP level was independently associated with all-cause death (HR: 1.58 per SD, 95%CI: 1.07-2.35) and CV death (HR: 1.61 per SD, 95%CI: 1.07-2.41)
- Longitudinal hsCRP increases were also independently associated with MACE (HR: 1.15 per SD, 95%CI: 1.09-1.21), and with all-cause death (HR: 1.25 per SD, 95%CI: 1.18-1.32) and CV death (HR: 1.26 per SD, 95%CI: 1.19-1.34).
- In a multivariable analysis of factors associated with changes in longitudinal hsCRP levels, baseline hsCRP, age, BMI, hypertension, congestive HF and active smoking showed significant positive associations. Significant negative associations were seen for male sex, baseline antiplatelet use, baseline HDL-c, varespladib treatment, high-intensity statin therapy use.
These data support previous observations that hsCRP levels measured at the time of ACS are associated with future CV events. Moreover, they suggest that an increase in hsCRP levels after ACS is associated with risk for MACE, CV death and all-cause death. These observations were independent of baseline hsCRP level and assigned treatment VISTA-16 trial, and optimal evidence-based medical therapies.