Current guidelines recommend risk stratification largely based on traditional risk factors such as those in the Framingham Risk Score. We studied the distribution of 12 traditional and non-traditional risk markers (age ≥65 years, male gender, family history of premature coronary heart disease, low-density lipoprotein cholesterol ≥70 mg/dl, high-density lipoprotein cholesterol <40 mg/dl in men and <50 mg/dl in women, systolic blood pressure >130 mm Hg, diabetes mellitus, smoking, C-reactive protein ≥2 mg/L, triglycerides >150 mg/dl, prediabetes defined as a fasting glucose level 100 to 125 mg/dl or hemoglobin A1c >6, and obesity defined as body mass index ≥30 kg/m 2 ) in 3,675 patients from the PROVE IT-TIMI 22 trial at 4 months and evaluated the risk of cardiovascular events stratified by the number of risk factors. The median number of risk factors was 5. In individual risk factor subgroups, men, smokers, hypertensives, and patients with increased low-density lipoprotein cholesterol had just that added risk factor compared to their counterparts (median 5 vs 4). In contrast, patients with diabetes, prediabetes, and increased triglycerides, C-reactive protein, or body mass index had not only that, but also another added risk factor (median 6 vs 4). A higher risk factor count was strongly related with increased rate of death, myocardial infarction, unstable angina, stroke, or revascularization, from 0% to 38.6% at 2 years for 0 to ≥9 risk factors (p <0.0001). In conclusion, with the observed “clustering” of risk factors and the link between increasing risk factor count and adverse outcomes in a patient with 1 diagnosed risk factor, a comprehensive review of traditional and novel risk factors is important to fully assess cardiovascular risk.
The traditional risk factors identified in the Framingham Risk Score (age, total cholesterol, high-density lipoprotein [HDL] cholesterol, systolic blood pressure, diabetes, and smoking) are widely used for estimation of the 10-year likelihood of developing coronary heart disease (CHD). However, 15% to 20% of patients develop CHD in the absence of these traditional risk factors. Conversely, in patients who remain free from CHD throughout their lives, most have ≥1 classic risk factor. Thus, conventional risk factors alone do not adequately explain the occurrence of cardiovascular events in the general population. Although the National Cholesterol Education Program–Adult Treatment Panel III risk assessment pathway incorporates the traditional risk factors, other emerging cardiometabolic risk predictors, such as triglycerides (TGs), abdominal adiposity, and insulin resistance or “prediabetes” and markers of inflammation (such as high-sensitivity C-reactive protein [CRP]) remain excluded, which have a well-defined independent effect on global cardiometabolic risk. These nontraditional risk factors may be present in patients without other more traditional risk factors and therefore an evaluation that assesses only for traditional risk factors may fail to identify many patients at increased risk for adverse cardiovascular outcomes. We sought to evaluate whether including nontraditional risk factors as part of a simple cardiovascular risk evaluation would be helpful.
Methods
The design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) protocol has been previously described. Briefly, 4,162 patients who had been hospitalized for an acute coronary syndrome within the previous 10 days and were stable for ≥24 hours were enrolled from November 2000 to December 2001 and were randomized in a 2 × 2 factorial design to pravastatin 40 mg (standard therapy) or atorvastatin 80 mg/day (intensive therapy) and gatifloxacin versus placebo. To be eligible, subjects had to have a total cholesterol level of ≤240 or <200 mg/dl if they were on previous lipid-lowering therapy. Subjects were followed for a mean of 24 months. The primary outcome was the time from randomization to the first occurrence of death from any cause, myocardial infarction, documented unstable angina pectoris requiring hospitalization, revascularization with percutaneous coronary intervention or coronary artery bypass grafting performed 30 days after randomization, and stroke. All end points were adjudicated independently by a clinical events committee blinded to treatment assignment.
Total cholesterol, HDL cholesterol, and TG were measured in fasting samples at the core laboratories using an enzymatic colorimetric method and the Roche Modular System (LabCorp, Raritan, New Jersey). Low-density lipoprotein (LDL) cholesterol level was obtained by calculation (total cholesterol − [TG/5 + HDL cholesterol]). If TG were increased, direct LDL cholesterol was measured. CRP level was measured using the validated Denka Seiken assay for high-sensitivity CRP (Children’s Hospital, Boston, Massachusetts). Height and smoking status were measured at enrollment, and blood pressure and weight were recorded at each visit.
Twelve risk markers were assessed for this analysis. These included the standard risk factors, namely age ≥65 years, male gender, family history of premature CHD, LDL cholesterol ≥70 mg/dl, HDL cholesterol <40 mg/dl in men and <50 mg/dl in women, systolic blood pressure >130 mm Hg, diabetes, and smoking status and emerging risk factors, namely CRP ≥2 mg/L, TG >150 mg/dl, prediabetes (defined as fasting glucose 100 to 125 mg/dl or hemoglobin A1c >6), and obesity (defined as body mass index ≥30 kg/m 2 ). Because lipid, CRP, and glucose levels in the setting of acute coronary syndrome may not represent actual baseline levels, we included only those patients in whom these measurements were available at 4 months (n = 3,675) for this cross-sectional analysis. Subjects were stratified into 10 groups (0 to ≥9) based on number of risk factors present. Cardiovascular events were left censored at the 4-month time point for the present study and only events occurring thereafter were included. Log-rank testing for trend was used to determine if a greater risk factor count was associated with increased rates of the primary end point and the secondary outcome of death/myocardial infarction/stroke. To examine the distribution of risk factors in our cohort, we constructed patient subgroups based on presence or absence of individual risk factors for each of the 12 markers under study. These subgroups were subsequently similarly stratified into 10 groups (0 to ≥9) based on risk factor count.
Results
The distribution of number of risk factors in the overall cohort is illustrated in Figure 1 . Overall, participants had a median of 5 risk factors. Distribution of risk factor count in patient subgroups with or without each of the 12 traditional and novel risk factors is shown in Figure 2 . Subjects ≥65 years old had a median of 5 risk factors, as did those <65 years of age. Men, smokers, hypertensives, patients with a family history of premature CHD, those with increased LDL cholesterol, and those with low HDL cholesterol had a median of 5 risk markers compared to 4 in patients without these risk factors (women, nonsmokers, nonhypertensives, patients without premature CHD in the family, those with LDL cholesterol <70 mg/dl, and those with increased HDL cholesterol). Thus, they had just that added risk factor compared to their counterparts. However, for patients with diabetes, prediabetes, or increased TG, CRP, or body mass index, median risk factor count was 6 compared to their counterparts (patients without diabetes or prediabetes or with typical TG, CRP, or body mass index) who had just 4 risk factors. Thus, these patients had not only that, but also another additional risk factor.
The association of number of risk factors with rates of adverse cardiovascular events is demonstrated in Figure 3 . A larger number of risk factors was strongly correlated with increased rates for the primary end point (p <0.0001). A similar relation was observed for the secondary outcome of death/myocardial infarction/stroke (p <0.0001).
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