C-Reactive Protein Levels and Cardiovascular Events after Acute Coronary Syndrome: Results from a Secondary Analysis of the VISTA-16 Trial

By Aly Becraft, MS; Kevin C Maki, PhD


Each year approximately 29% of heart attack (myocardial infarction) events in the USA occur in people who have previously had a heart attack.1 Even with ideal medical interventions and treatments, there is high risk of subsequent cardiac events and death in people that have suffered an acute coronary syndrome (ACS).2,3 This elevated risk may be lowered if specific biomarkers associated with future adverse cardiac events can be identified and used in long-term management following ACS. Several biomarkers of cardiovascular disease (CVD) are currently being studied, including those related to inflammation, a major contributor to the development of atherothrombosis. Well-studied inflammatory biomarkers include fibrinogen, monocyte chemotactic protein-1, tumor necrosis factor-alpha, C-reactive protein (CRP), and others.4

High-sensitivity CRP (hsCRP) measurement has become a routine and effective method for predicting risk of CVD and is also used as a prognostic marker after ACS.5 Lowered hsCRP levels in patients with chronic CVD treated with anti-inflammatory and statin therapies has been shown to improve treatment outcomes and lower risk of adverse cardiovascular events.3,6 Furthermore, other studies have reported a correlation between CRP levels and the effectiveness of statin treatment7,8 and high-dose statins have been demonstrated to accelerate decreases in hsCRP levels after ACS.9,10 While there is a substantial body of research demonstrating these associations, in order to optimize clinical use, the applications for hsCRP levels in the treatment of CVD are still being investigated.


Mani et al. recently published a secondary analysis of the Vascular Inflammation Suppression to Treat Acute Coronary Syndromes for 16 Weeks (VISTA-16) trial to assess whether longitudinal changes in hsCRP levels were associated with residual risk of cardiovascular events or death following ACS.11 This randomized, double blind, multicenter trial tested treatment of ACS with the secretory phospholipase A2 inhibitor, varespladib, in 5145 patients. Treatment began within 96 hours of an ACS. Only patients with qualifying baseline and longitudinal hsCRP levels measured at weeks 1, 2, 4, 8, and 16 weeks of the trial were used in this secondary analysis (n = 4257). The primary end point of this analysis was the association between hsCRP and a major adverse cardiac event (MACE) defined as the composite of cardiovascular death, non-fatal myocardial infarction, stroke, or hospitalization for unstable angina at 16 weeks. Secondary end points included the associations between hsCRP and individual components of the primary composite end point.11 The trial treatment had no significant effects on hsCRP level.


Analyzed patients were overweight, had a mean age of 60.3 years and 74% were male.11 Approximately 77% of the patients had hypertension, 51% had hypercholesterolemia and 65% had metabolic syndrome. In addition, 30% of patients had experienced a previous myocardial infarction, 18% had undergone percutaneous coronary intervention, and 36% of patients were using lipid-modifying therapy prior to the trial.


Of the 247 events observed in the VISTA-16 trial, 145 were included in this analysis.11 Baseline hsCRP levels following ACS were associated with higher risk for future MACE and death, as had been shown previously. Longitudinal increases in hsCRP levels were associated with significantly higher incidence of MACE [hazard ratio (HR) per SD 1.16, P < 0.001], myocardial infarction (HR 1.16, P < 0.001), all-cause death (HR 1.25, P < 0.001), and cardiovascular death (HR 1.26, P < 0.001). These relationships were not attenuated in multivariate models that adjusted for several other predictive variables and treatment assignment.  Positive associations between changes in longitudinal hsCRP levels and age (P = 0.03), body mass index (P < 0.001), hypertension (P < 0.001), congestive heart failure (P < 0.001), and active smoking (P = 0.003) were reported. 


Comment: These results suggest that measuring longitudinal changes in hsCRP levels after ACS is useful for assessing residual cardiovascular risk.  Higher baseline hsCRP after ACS and persistent hsCRP elevation were both independently associated with increased risks for MACE and individual MACE components, as well as CVD and total mortality.  Each SD increase in hsCRP during follow-up was associated with an increase of 15% in MACE, 25% in total mortality and 26% in CVD mortality.


The present study adds to previous findings, such as those from the Canakinumab Antiinflammatory Thrombosis Outcome Study,12 which demonstrated similar associations between higher hsCRP levels and adverse cardiovascular outcomes and mortality and further showed that an anti-inflammatory intervention reduced MACE risk. Similarly, results from epidemiological studies have suggested that increases in serial measurement of CRP in relatively healthy populations are associated with adverse cardiovascular outcomes and increased mortality.13,14 Further study is needed to evaluate longer-term outcomes and to assess the efficacy of various treatment modalities to lower MACE and mortality incidence in those identified as having elevated residual risk after ACS due to persistent hsCRP elevation.



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