Abstract
Background
Sex-based differences in the association between C-reactive protein (CRP) and cardiovascular events in patients with coronary artery disease (CAD) are incompletely investigated. We investigated whether there are gender differences in the association between CRP and outcome in patients with CAD after percutaneous coronary intervention (PCI).
Methods
This study included 13,170 consecutive patients with CAD: 10,098 men and 3072 women. CRP was measured on admission in all patients. The primary outcome was 1-year mortality.
Results
CRP level (median [25th–75th percentiles]) was higher in women than in men (3.08 [1.30–8.37] mg/L vs 2.30 [0.92–6.47] mg/L; P < 0.001). CRP was > 3 mg/L in 4250 men (42.1%) and 1554 women (50.6%; P < 0.001). One-year mortality was 4.9% (n = 641 deaths). Deaths occurred in 318 men with CRP > 3 mg/L and 122 men with CRP ≤ 3 mg/L (mortality estimates 7.7% and 2.1%, P < 0.001) and in 154 women with CRP > 3 mg/L and 47 women with CRP ≤ 3 mg/L (mortality estimates 10.1% and 3.2%, P < 0.001). After adjustment in the Cox model, CRP was associated with increased risk of mortality in women (adjusted hazard ratio [HR] = 1.03, 95% confidence interval [CI] 1.01–1.04, P < 0.001 for each 5 mg/L increase) and in men (adjusted HR = 1.02 [1.01–1.03], P < 0.001, for each 5 mg/L increase). CRP predicted mortality with an area under the receiver-operating characteristic curve = 0.721, [0.683–0.760] in women and 0.732, [0.707–0.757] in men (P = 0.659).
Conclusions
Elevated CRP levels provide similar prognostic information in men and women with CAD after PCI which is independent and supplementary to that provided by conventional cardiovascular risk factors.
1
Introduction
C-reactive protein (CRP) is the most extensively investigated marker of inflammation. Elevated levels of CRP predict increased cardiovascular morbidity and mortality among apparently healthy subjects and patients with CAD . Current guidelines suggest the use of CRP to risk stratify subjects at intermediate disk for cardiovascular disease (class IIa recommendation in men 50 years of age or older or women 60 years of age or older with low-density lipoprotein cholesterol < 130 mg/dL and class IIb recommendation in asymptomatic intermediate-risk men 50 years of age or younger or women 60 years of age or younger) . Several studies have reported higher CRP levels in women than in men . Nevertheless, sex-related differences in the association between CRP and cardiovascular events remain incompletely investigated. Studies that have investigated this issue have given conflicting results . A nested case–control study from the Nurses’ Health Study and Health Professionals Follow-up Study showed that elevated CRP level was associated with increased risk of CAD among men and women without previous cardiovascular disease . Conversely, 2 recent meta-analyses with large numbers of subjects showed a higher relative risk for an association between CRP and CAD in men than in women or that CRP and fibrinogen improved risk discrimination for cardiovascular disease only in men . Similar findings have also been reported for the association between fibrinogen and mortality . Sex-based analyses of the association between CRP and cardiovascular events in patients with CAD are limited and their findings are conflicting . Thus, we undertook this study to investigate the prognostic power of CRP in men and women with CAD after percutaneous coronary intervention (PCI) and to assess whether the strength of association between CRP and outcome differs according to sex.
2
Methods
2.1
Patients
This study included 13,170 consecutive patients with coronary angiography confirmation of significant CAD who underwent PCI in our hospital between March 2000 and December 2009. Of them, 10,098 patients were men and 3072 were women. The majority of patients were with stable CAD (56.3% of women and 63.0% of men). Patients without CRP measurements and those with acute infections, advanced renal disease (serum creatinine ≥ 2 mg/dl), malignancies with life expectancy < 1 year, pregnancy or contraindications to perform angiographic examination were excluded. All patients gave written informed consent for angiographic examination and eventual PCI and blood sampling. The study conforms to the Declaration of Helsinki and was approved by the institutional ethics committee.
2.2
Definitions
CAD was confirmed if coronary stenoses with ≥ 50% lumen obstruction in, at least, one of the three major coronary arteries were confirmed by coronary angiography. Left ventricular ejection fraction was measured using left ventricular angiograms according to the method by Sandler and Dodge . Digital angiograms were analyzed offline with an automated edge detection system (CMS; Medis Medical Imaging Systems, Nuenen, The Netherlands) in the core angiographic laboratory by laboratory personnel unaware of CRP level. Cardiovascular risk factors (arterial hypertension, hypercholesterolemia, diabetes and smoking) were defined using accepted criteria. Hypercholesterolemia was defined as a total cholesterol of ≥ 220 mg/dl or prior or ongoing treatment with lipid lowering agents; arterial hypertension was diagnosed if patients were under active treatment with antihypertensive drugs or if the systolic blood pressure was ≥ 140 mmHg or the diastolic blood pressure ≥ 90 mmHg on, at least, 2 separate occasions; diabetes was diagnosed in the presence of: active treatment with insulin or an oral hypoglycemic agent; an abnormal fasting blood glucose test (glucose ≥ 126 mg/dl or ≥ 7.0 mmol/dl); a blood glucose > 200 mg/dl (> 11.1 mmol/dl) at any time; or an abnormal 2-h post glucose load test according to the World Health Organization criteria; current smokers were those with regular smoking in the prior 6 months. Obesity was assessed by calculating the body mass index with patients’ weight and height measured during the hospital course. The glomerular filtration rate was estimated by calculating the creatinine clearance according to the Cockcroft–Gault equation .
PCI mostly consisted of coronary stenting (11,915 patients, 90.5%). PCI was performed according to standard practice. Unfractionated heparin or bivalirudin was used for periprocedural anticoagulation. Periprocedural antithrombotic treatment included aspirin (325 to 500 mg) and clopidogrel (300 mg or 600 mg as loading dose). Postprocedural antithrombotic therapy consisted of clopidogrel (75 mg/day for at least 1 month in patients with bare metal stents and up to 1 year in patients with drug-eluting stents) and aspirin (200 mg/day indefinitely).
2.3
C-reactive Protein Measurements
Blood samples were obtained before angiography in tubes containing ethylenediaminetetraacetic acid or lithium–heparin as anticoagulant. Plasma high-sensitivity CRP was measured using a fully automated latex-enhanced immunoturbidimetric assay on a Cobas Integra (Roche Diagnostics, Mannheim, Germany). The assay has an analytical sensitivity of 0.085 mg/L. The upper limit of the reference range in healthy adults is 5 mg/L.
Based on prior studies, a CRP cutoff of 3 mg/L was used to classify patients into groups with high CRP (CRP level > 3 mg/L) and low CRP (CRP level ≤ 3 mg/L) level. Laboratory personnel were unaware of clinical diagnosis and not involved in the follow-up of the patients.
2.4
Outcomes and follow-up
The main outcome was 1-year mortality in men and women. Other outcomes of interest were 1-year incidences of cardiac mortality, nonfatal myocardial infarction, stroke and stent thrombosis. The follow-up protocol included: a phone interview at 1 month, a visit at 6 months and another phone interview at 12 months after hospital discharge. Information on mortality was obtained using hospital charts, death certificates or phone contact with relatives of the patient or referring physician(s). Deaths of cardiac origin and stent thrombosis were defined according to the Academic Research Consortium criteria . Myocardial infarction was diagnosed if patients developed new abnormal Q waves in > 2 contiguous precordial or > 2 adjacent limb leads or if they had an elevation of creatine kinase-myocardial band (CK-MB) > 2 times (> 3 times for the first 48 h after PCI procedure) the upper limit of normal. Stroke was diagnosed in the presence of newly developed neurological deficits confirmed by imaging of the head. All follow-up information and adjudication of events were performed by personnel unaware of clinical diagnosis or CRP level.
2.5
Statistical analysis
Data are presented as median (25th; 75th percentiles), number of patients/events or proportions (%). The normality of data distribution was tested with the Kolmogorov–Smirnov test. Continuous data with skewed distribution were compared with the Kruskal–Wallis rank-sum test. Categorical data were compared with Chi-square test. Survival analysis was performed by applying the Kaplan–Meier method and the differences in survival were compared with the log-rank test. The multivariable Cox proportional hazards model was used to assess the association between CRP and mortality in men and women. All variables of Table 1 were entered into the model. Receiver-operating characteristic (ROC) curve analysis was performed to compare the discriminatory power of CRP regarding mortality prediction in men versus women. Comparison of the respective areas under the ROC curve was performed using the pROC package with bootstrapping method (n = 1000 samples). The discriminatory power of the multivariable models before and after CRP inclusion was performed by calculating the Harrell’s c index. The c indexes were compared with the Somer’s D package. Analyses were performed using S-plus statistical package (S-PLUS, Insightful Corp, Seattle, Washington) or R-package. A 2-sided P < 0.05 was considered to indicate statistical significance.
