Inflammation and Long-Term Mortality After Non–ST Elevation Acute Coronary Syndrome Treated With a Very Early Invasive Strategy in 1042 Consecutive Patients
Background— This study sought to evaluate the predictive value of C-reactive protein (CRP) on long-term mortality in non–ST-elevation acute coronary syndromes (NSTACS) that were treated with a very early aggressive revascularization strategy.
Methods and Results— We conducted a prospective cohort study in 1042 consecutive patients with NSTACS who were undergoing coronary angiography and subsequent coronary stenting of the culprit lesion as the primary revascularization strategy within 24 hours. Levels of CRP were determined on admission. The patients were followed for a mean of 20 months. In-hospital mortality was significantly higher in patients with a CRP>10 mg/L (3.7% versus 1.2% with CRP<3 mg/L and versus 0.8% with CRP of 3 to 10 mg/L; relative risk for CRP>10 mg/L compared with CRP≤10 mg/L was 4.2, 95% confidence interval [CI] was 1.6 to 11.0; P=0.004). The increase in mortality in patients with CRP>10 mg/L persisted during follow-up. Long-term mortality was 3.4% with CRP<3 mg/L, 4.4% with CRP between 3 and 10 mg/L, and 12.7% with CRP>10 mg/L (relative risk for CRP>10 mg/L compared with CRP≤10 mg/L, 0.8; 95% CI, 2.3 to 6.2; P<0.001). In addition, Kaplan-Meier survival analysis demonstrated a significantly reduced survival at 4 years in patients with a CRP>10 mg/L (78% versus 88% for a CRP of 3 to 10 mg/L and versus 92% for CRP<3 mg/L; P<0.001 by log-rank). In a multivariate analysis, CRP was an independent predictor of long-term mortality. Patients with a CRP>10 mg/L had >4 times the risk of death (odds ratio, 4.1; 95% CI, 2.3 to 7.2).
Conclusion— CRP is a strong independent predictor of short and long-term mortality after NSTACS that are treated with very early revascularization.
Received December 12, 2001; revision received January 29, 2002; accepted January 29, 2002.
The contribution of inflammation to the initiation of unstable coronary artery disease1 has attained increasing recognition. C-reactive protein (CRP), an acute-phase reactant that reflects low-grade systemic inflammation, has been shown to be related to adverse outcome in non–ST-elevation acute coronary syndromes (NSTACS).2–7⇓⇓⇓⇓⇓ In the FRISC study,6 the rate of death from cardiac causes was increased 2-fold with a CRP>10 mg/L. Patients in these studies were primarily treated conservatively with anti-ischemic and antithrombotic medication. Coronary angiography was performed only after “cooling down” on medical therapy and was restricted to patients with recurrent ischemia.
Very early revascularization has been proposed as a novel, potentially superior management strategy in patients with NSTACS.8,9⇓ Predictors of long-term mortality in patients with NSTACS who are treated with an aggressive, very early invasive strategy remain to be established.
We sought to determine if very early revascularization might ameliorate the negative prognostic impact of elevated CRP.
From January 1996 to December 1999, consecutive patients admitted to our center with NSTACS were treated with coronary angiography and subsequent coronary stenting of the culprit lesion as the primary revascularization strategy within 24 hours. If percutaneous coronary intervention (PCI) was not possible (unprotected left main disease or diffuse 3-vessel disease) but revascularization seemed necessary, patients were scheduled for urgent coronary artery bypass grafting (CABG). Excluded from this analysis were only 11 patients in whom angiography was not performed due to patient refusal (n=5) or extremely severe concomitant disease (n=6). At hospital discharge, all patients were strongly counseled to follow a low-cholesterol diet, and statins were recommended to achieve an LDL-cholesterol <100 mg/dL during follow-up.
The study was performed according to the principles of the Declaration of Helsinki. Informed consent was obtained from all participating patients.
Blood Sampling and Laboratory Methods
Levels of CRP were determined on hospital admission by turbidimetry6 (Hitachi model 717, Roche Diagnostics GmbH). The lower detection limit of this test is 3 mg/L. The treating physician was not blinded to the CRP values.
All patients were evaluated at 6 months. In addition, patients were contacted by questionnaire and hospital records were reviewed in September 2000, nearly 5 years after the first patient was enrolled. The medical records of patients suffering adverse events at other hospitals were also obtained and reviewed.
End Points and Statistical Analysis
The primary end point was death from any cause. CRP cut points were chosen to reflect those used in previous studies.2–7⇓⇓⇓⇓⇓ Statistical analyses was performed using SPSS version 10.0. Discrete variables were expressed as percentage (95% confidence interval [CI]), continuous variables as means (95% CI), and a significance level of 0.05 was used. Comparisons were made using ANOVA for independent samples and χ2 tests as appropriate. All hypothesis testing was 2-tailed. Cox proportional-hazards regression analysis was used. Univariate and multivariate Cox regression analyses were performed to find significant predictors of survival, including the variables CRP>10 mg/L, troponin T ≥0.1 μg/L, ECG findings, number of coronary vessels with ≥50% stenosis, and baseline characteristics. Survival curves were generated with the Kaplan-Meier estimator.
A total of 1042 consecutive patients had quantitative CRP assays performed on admission (Table 1). In the group with a CRP>10 mg/L, patients were older and more often had non-Q-wave myocardial infarction, elevated troponin levels, and 3-vessel coronary artery disease; they also had higher levels of serum creatinine and platelet count. These patients were less likely to have had prior PCI and were less likely to have no high grade coronary lesion on angiography.
The majority of patients in all CRP groups received very early PCI with stent implantation. Because of the higher incidence of severe diffuse disease, CABG had to be performed more often as the primary revascularization procedure in patients with a CRP>10 mg/L.
A total of 64 deaths occurred during a mean follow-up of 20 months (range, 1 to 60 months). In-hospital mortality (Table 2) was significantly higher in patients with a CRP>10 mg/L (3.7% versus 1.2% with CRP<3 mg/L and versus 0.8% with CRP of 3 to 10 mg/L) The relative risk for CRP>10 mg/L compared with CRP≤10 mg/L was 0.2 (95% CI, 1.6 to 11.0; P=0.004). The increase in mortality in patients with CRP>10 mg/L persisted during follow-up. Long-term mortality was 3.4% with CRP<3 mg/L, 4.4% with CRP between 3 and 10 mg/L, and 12.7 with CRP>10 mg/L. The relative risk for CRP>10 mg/L compared with CRP ≤10 mg/L was 0.8 (95% CI, 2.3 to 6.2; P<0.001). Kaplan-Meier survival analysis demonstrated a significantly reduced survival at 4 years in patients with CRP>10 mg/L (78% versus 92% with CRP<3 mg/L and versus 88% with CRP of 3 to 10 mg/L; P<0.001 by log-rank; Figure).
Univariate Cox regression analysis (Table 3) showed interesting associations between long-term mortality and potential risk factors. CRP was significantly higher in patients who died than in survivors (34 versus 10 mg/L; P<0.001). Backward-stepwise multivariate Cox regression analysis identified CRP, ST-segment depression, T-wave inversion, age, female sex, serum creatinine, platelet count, and the number of coronary arteries with ≥50% stenosis as independent predictors of long-term mortality (Table 4). In this model, CRP>10 mg/L had the strongest impact, with an odds ratio of 4.1 (95% CI, 2.3 to 7.2).
This large study of 1042 consecutive patients with NSTACS treated with an aggressive revascularization strategy confirmed CRP as a strong independent predictor of long-term mortality and thereby extends this important finding to the most contemporary revascularization strategy. This is of clinical importance because it encourages the use of this powerful parameter for the risk stratification of patients with NSTACS. Patients with CRP>10 mg/L should receive particular attention because they have a 4-fold increase in in-hospital and long-term mortality. In addition, our results highlight the importance of inflammation in the setting of NSTACS and may help guide the development of novel anti-inflammatory therapies. Our analysis has 2 particular strengths. First, it is derived from a prospective study of consecutive, unselected patients rather than a randomized trial.3–7⇓⇓⇓⇓ This eliminates selection bias and allows extrapolation of findings into clinical practice. Second, the extent of coronary artery disease was quantified in all patients and was included in the multivariate analysis.
The findings of this study are in agreement with previous reports showing an independent prognostic role for CRP in patients with NSTACS who are primarily treated conservatively.2–7⇓⇓⇓⇓⇓ Very early revascularization does not ameliorate the negative prognostic impact of elevated CRP. In contrast, CRP seems to be an even more potent predictor of mortality with this strategy. This might be due to the fact that CRP might not only mirror an underlying inflammatory process in the plaque,10 but also directly participate in complement activation, tissue damage,11 and the expression of adhesion molecules and chemokines12 in human endothelial cells. These mechanisms seem to be particularly detrimental after very early revascularization. It is important to note that the excess risk in patients with CRP>10 mg/L in this study persisted despite a strict adherence to current secondary prevention guidelines, including the use of statins.13 A conventional CRP assay was used in this study. With the cut-off points used, it is unlikely that a high-sensitivity assay would have changed the results.
In conclusion, CRP is a strong independent predictor of long-term mortality in patients with NSTACS. A strategy of very early revascularization does not ameliorate this relationship.
- ↵Yeh ET, Anderson V, Pasceri V, et al. C-reactive protein: linking inflammation to cardiovascular complications. Circulation. 2001; 104: 974–975.
- ↵Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.