Abstract
Elevated high‐sensitivity C‐reactive protein (hs‐CRP) is associated with worse cardiovascular outcomes in patients with acute myocardial infarction (AMI), but little is known about the distribution of hs‐CRP levels and predictors of elevated hs‐CRP after AMI in the real world. Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) and Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) are prospective AMI registries in the United States that assessed hs‐CRP levels 30 days after AMI. TRIUMPH additionally assessed hs‐CRP levels at the time of AMI and at 6 months. Hierarchical models were built to examine predictors of elevated hs‐CRP (≥2.0 mg/L) at 30 days in both registries and at 6 months after AMI in TRIUMPH. Of 3410 patients in both registries, 58.6% had elevated hs‐CRP 30 days after AMI. Patients with elevated hs‐CRP at 30 days were more likely to be older, female, obese, smokers, report financial difficulties, and have higher low‐density lipoprotein cholesterol levels on admission, diabetes, and hypertension. In TRIUMPH, baseline hs‐CRP ≥2 mg/L (n = 1301) was significantly associated with elevated hs‐CRP at follow‐up (P < 0.001). Similar associations were found in TRIUMPH patients with elevated hs‐CRP at 6 months. Our study identified a high prevalence and several patient characteristics associated with elevated hs‐CRP at 1 and 6 months after discharge. Further studies to test routine screening after AMI may be warranted to identify higher‐risk patients for more aggressive secondary prevention.
Keywords: Acute Myocardial Infarction, High‐Sensitivity C‐Reactive Protein, Risk Factors
1. INTRODUCTION
C‐reactive protein, which can be measured with a high‐sensitivity C‐reactive protein (hs‐CRP) assay, is an acute‐phase reactant that is an established marker of cardiovascular risk.1, 2 Reduction of hs‐CRP using statin therapy was associated with improved cardiovascular outcomes in patients with no prior history of coronary artery disease.3 Furthermore, in patients recovering from acute myocardial infarction (AMI) who had elevated hs‐CRP levels, reduction of hs‐CRP level to <2 mg/L was associated with improved long‐term cardiovascular outcomes compared with those with a higher hs‐CRP level.4 Moreover, multiple studies reported the predictive ability (for all‐cause mortality, cardiovascular death, heart failure, and rehospitalizations) of hs‐CRP after acute coronary syndromes5, 6, 7, 8, 9, 10; however, hs‐CRP is still not checked routinely after AMI, and the prevalence and predictors of elevated hs‐CRP in this population is understudied in the real world.
Given that hs‐CRP is a clinical marker of potentially modifiable risk in patients with coronary artery disease, efficient strategies are needed to identify patients likely to have elevated hs‐CRP who could be candidates for more aggressive treatment. However, little is known about the distribution of persistently elevated inflammatory markers in patients following AMI in a real‐world population. Thus, insights into the characteristics of patients with elevated hs‐CRP after a recent AMI are needed to better design follow‐up surveillance and treatment strategies for high‐risk patients. Accordingly, we leveraged the Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health Status (TRIUMPH)11 and Variation in Recovery Role of Gender on Outcomes of Young AMI Patients (VIRGO)12 studies to describe the prevalence of elevated hs‐CRP following recent AMI and to examine the patient characteristics associated with elevated hs‐CRP levels after AMI.
2. METHODS
2.1. Study design and population
For this study, data from the TRIUMPH11 and VIRGO12 registries were used. The methodology of the TRIUMPH and the VIRGO registries has been previously published and included data collected from both chart abstraction and patient interviews. In brief, TRIUMPH was a prospective observational, 24‐center AMI registry that recruited patients with AMI from diverse geographical regions throughout the United States between April 11, 2005 and December 31, 2008. Inclusion criteria were age ≥ 18 years, having elevated cardiac enzymes (creatinine kinase‐myocardial band or troponin‐I) within 24 hours of hospital admission, and a diagnosis of an AMI, including long‐standing ischemic symptoms or electrocardiographic ST changes. Patients excluded were those who were transferred to the enrolling hospital from another facility after more than 24 hours and those patients who were incarcerated, refused to participate, developed elevated cardiac markers because of elective coronary revascularization, were not able to provide informed consent, or did not speak English or Spanish.
The VIRGO registry (August 21, 2008 to January 5, 2012) was a prospective observational registry of 18‐ to 55‐year‐old patients with AMI enrolled using a 2:1 female:male ratio from 103 US and 24 Spanish hospitals.12 Eligible patients had elevated cardiac biomarkers (troponin I or T or creatine kinase‐myocardial band), with at least 1 biomarker >99th percentile of the upper reference limit at the recruiting center within 24 hours of admission (>97% of patients had qualifying troponin levels). Additional evidence of acute myocardial ischemia was required, including either symptoms of ischemia or electrocardiogram changes indicative of new ischemia (new ST‐T changes, new or presumably new left bundle branch block, or the development of pathological Q waves).13 Patients must have presented directly to the enrolling site or been transferred within the first 24 hours of presentation. Patients who were incarcerated, did not speak English or Spanish, were unable to provide informed consent or be contacted for follow‐up, developed elevated cardiac markers because of elective coronary revascularization, or had an AMI as the result of physical trauma were not eligible.
2.2. hs‐CRP data
An optional component of the TRIUMPH registry was to participate in a bloodwork substudy, with collection at the time of AMI hospitalization and optionally at 30 days and 6 months later through home visits by trained paramedics. VIRGO collected hs‐CRP levels only at 30 days after AMI, without collection at the time of AMI admission or 6 months later.
For the current analyses, elevated hs‐CRP was defined as ≥2.0 mg/L concurrent with ongoing and prior clinical trials including CANTOS (A Randomized, Double‐blind, Placebo‐controlled, Event‐driven Trial of Quarterly Subcutaneous Canakinumab in the Prevention of Recurrent Cardiovascular Events Among Stable Post‐myocardial Infarction Patients With Elevated hsCRP), IMPROVE‐IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), and JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin).3, 14, 15 However, the guideline statement about the clinical characteristics and utilization of biochemical markers in acute coronary syndromes16 suggested that when hs‐CRP is tested 1 or more months after presentation with ACS, use of cut points (low: <1 mg/L, intermediate 1–3 mg/L, high: >3 mg/L) is recommended. Moreover, other population studies and Centers for Disease Control and Prevention/American Heart Association guidelines for coronary artery disease prevention17 identified an hs‐CRP of ≥3.0 mg/L to be associated with high risk for cardiovascular events. Thus, sensitivity analyses were performed using a definition of elevated hs‐CRP to be ≥3.0 mg/L.
2.3. Study outcomes
The main objectives of this study were to document the prevalence of elevated hs‐CRP levels at 30 days post AMI hospitalization, and to describe patient characteristics associated with elevated hs‐CRP 30 days after AMI. Exploratory analyses were also conducted in TRIUMPH to describe patient characteristics associated with elevated hs‐CRP at 6 months and to examine the association of hs‐CRP levels at the time of AMI hospitalization with 30‐day and 6‐month hs‐CRP levels, as well as persistently elevated hs‐CRP (elevated both at 30 days and 6 months post‐AMI).
2.4. Statistical methods
Demographic and clinical characteristics were compared between patients with and without elevated hs‐CRP (≥2.0 mg/L) at 30 days (TRIUMPH and VIRGO) after AMI using independent t tests for continuous variables and χ2 tests for categorical variables. Patterns of elevated hs‐CRP at 30 days (TRIUMPH and VIRGO) and baseline and 6 months (TRIUMPH only) were reported as percentages. To examine the predictors of elevated hs‐CRP at follow‐up (30 days, 6 months, and both 30 days and 6 months), we used 2‐level hierarchical logistic regression models (patients nested within the hospital) with study as a random‐level effect. This allowed us to handle the different selection processes of the 2 registries (primarily age and gender restrictions in VIRGO) and to create more generalizable estimates of the association of patient factors with elevated hs‐CRP at follow‐up. The data met all the statistical assumptions for modeling. Time 0 for assessing patient characteristics was hospital discharge, thus including all data acquired during the index hospitalization. An exception to this rule includes low‐density lipoprotein (LDL‐C) levels, which were collected closer to admission time when they are usually available for clinicians to use. Backward variable selection with retention of variables at P = 0.05 was used to identify risk factors independently associated with elevated hs‐CRP levels. Variables included in the models were selected a priori, based on literature review and clinical judgment (balanced against concerns of overfitting), and included the following: age, sex, race, financial status, body mass index, admission with non–ST‐elevation myocardial infarction (NSTEMI) vs ST‐elevation myocardial infarction, in‐hospital revascularization procedure, cardiac comorbidities (history of diabetes mellitus, hypertension, hyperlipidemia, peripheral vascular disease, heart failure, atrial fibrillation, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, and smoking), history of cerebrovascular accident, history of lung disease, alcohol use, left ventricular ejection fraction, creatinine, low‐density lipoprotein levels, and use of a statin medication. hs‐CRP level at baseline was included as a variable in the models conducted from TRIUMPH only, as were predictors of elevated hs‐CRP at 6 months and persistently elevated hs‐CRP (at both 30 days and 6 months after AMI). As a sensitivity analysis, we repeated all the analyses after changing the definition of elevated hs‐CRP to ≥3.0 mg/L (instead of ≥2.0 mg/L). Multiple imputation using Imputation and Variance Estimation Software (University of Michigan, Ann Arbor, MI) was conducted to impute missing variables (<11% missing information for all variables). All statistical analyses were performed with SAS version 9.4 (SAS Institute, Inc., Cary, NC).
3. RESULTS
3.1. Patient characteristics
Of 4340 patients enrolled in TRIUMPH, 1301 patients (30%) had 30‐day hs‐CRP levels, of whom 801 also had a baseline hs‐CRP level. Of 3501 patients enrolled in VIRGO, 2109 patients (60%) had 30‐day hs‐CRP levels (Figure 1). Patients' characteristics of those with no hs‐CRP levels at 30 days are reported in Supporting Table 1 in the online version of this article. Compared to patients in TRIUMPH, patients enrolled in VIRGO were more likely to be female, white, avoid care due to cost, to have a diagnosis of lung disease, hyperlipidemia, atrial fibrillation, a smoker, to have higher body mass index (BMI), to have been discharged on a statin, to have an elevated hs‐CRP at 30 days, and were less likely to receive revascularization during the AMI hospitalization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]), chronic kidney disease, congestive heart failure, or peripheral vascular disease (see Supporting Table 2 in the online version of this article).
Figure 1.
Flowchart of the analytic cohort. Abbreviations: hs‐CRP, high‐sensitivity C‐reactive protein; TRIUMPH, Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health Status; VIRGO, Variation in Recovery Role of Gender on Outcomes of Young AMI Patients
When TRIUPMH and VIRGO were combined there were a total of 3410 patients with available 30‐day hs‐CRP levels that formed the primary analytic cohort (Figure 1). Almost 59% of patients had elevated hs‐CRP at 30 days, with a median (interquartile range level of 2.6 (1.1–6.1) mg/L. Table 1 summarizes the characteristics of patients with and without elevated hs‐CRP (≥2.0 mg/L). The mean age of patients was 52 years, 54% were female, and 76% were white. Cardiac and noncardiac comorbidities were common, with prior myocardial infarction in 20%, prior PCI in 17%, prior CABG in 6.8%, diabetes in 29%, and chronic lung disease in 9%. In univariate analysis, patients with elevated hs‐CRP levels at 30 days were more likely to be female, black, to report financial difficulties, to have more comorbidities (chronic lung disease, prior MI, prior cerebrovascular accident, hypertension, diabetes, hyperlipidemia, congestive heart failure, peripheral vascular disease, prior percutaneous coronary intervention, smoking, obese), to have undergone CABG, with higher LDL levels, and to have an NSTEMI on presentation (Table 1). In TRIUMPH, those with an elevated hs‐CRP at 30 days also had higher baseline hs‐CRP values.
Table 1.
Characteristics of patients with and without elevated hs‐CRP (≥2.0 mg/L)
| hs‐CRP ≥2, n = 1999 | hs‐CRP <2, n = 1411 | Total, n = 3410 | P Value | |
|---|---|---|---|---|
| Age, y, mean ± SD | 51.9 ± 10.4 | 52.4 ± 10.8 | 52.1 ± 10.6 | 0.228 |
| Male | 41.5% | 52.9% | 46.2% | <0.001 |
| White race | 74.1% | 78.6% | 76.0% | <0.001 |
| BMI on admission, mean ± SD | 32.5 ± 7.5 | 28.7 ± 5.9 | 30.9 ± 7.1 | <0.001 |
| Self‐reported avoidance of care due to cost | 34.1% | 24.4% | 30.0% | <0.001 |
| Diagnosis on arrival | 0.016 | |||
| STEMI | 47.4% | 51.5% | 49.1% | |
| NSTEMI | 52.6% | 48.5% | 50.9% | |
| In‐hospital revascularization | 81.2% | 79.6% | 80.5% | 0.236 |
| Hypertension | 70.8% | 58.5% | 65.7% | <0.001 |
| Heart failure | 5.9% | 2.7% | 4.5% | <0.001 |
| History of myocardial infraction | 22.5% | 16.8% | 20.1% | <0.001 |
| Dyslipidemia | 64.5% | 57.1% | 61.5% | <0.001 |
| Chronic lung disease | 10.8% | 7.5% | 9.4% | 0.001 |
| Diabetes mellitus | 34.1% | 20.4% | 28.4% | <0.001 |
| Chronic kidney disease | 3.3% | 2.2% | 2.8% | 0.066 |
| Peripheral vascular disease | 3.9% | 1.9% | 3.1% | 0.001 |
| Atrial fibrillation | 6.0% | 6.0% | 6.0% | 0.988 |
| Smoking | 71.3% | 57.1% | 61.5% | <0.001 |
| Statin at discharge | 92.5% | 91.9% | 92.3% | 0.532 |
| Statin intensity on discharge | 0.336 | |||
| Low | 3.6% | 3.9% | 3.7% | |
| Moderate | 46.9% | 42.4% | 44.9% | |
| High | 49.5% | 53.7% | 51.4% | |
| Creatinine, mean ± SD | 1.0 ± 0.8 | 1.0 ± 0.6 | 1.0 ± 0.7 | 0.311 |
| Baseline LDL, mean ± SD | 112.9 ± 42.0 | 106.3 ± 40.5 | 110.1 ± 41.5 | <0.001 |
| Baseline LDL <100 mg/dL | 42.1% | 52.1% | 46.2% | <0.001 |
| Baseline LDL <70 mg/dL | 13.7% | 17.4% | 15.2% | 0.008 |
| hs‐CRP at baseline | <0.001 | |||
| Mean ± SD | 44.7 ± 56.0 | 24.5 ± 34.8 | 35.6 ± 48.6 | |
| Median (IQR) | 28.3 (12.0–52.6) | 11.4 (3.9–29.7) | 19.3 (7.1–44.9) | |
| hs‐CRP at 1 month | <0.001 | |||
| Mean ± SD | 9.7 ± 16.9 | 1.0 ± 0.5 | 6.1 ± 13.6 | |
| Median (IQR) | 5.2 (3.2–9.2) | 0.9 (0.6–1.4) | 2.6 (1.1–6.1) |
Abbreviations: BMI, body mass index; hs‐CRP, high‐sensitivity C‐reactive protein; IQR, interquartile range; LDL, low‐density lipoprotein; NSTEMI, non–ST‐elevation myocardial infarction; SD, standard deviation; STEMI, ST‐elevation myocardial infarction.
3.2. Distribution of hs‐CRP levels in post‐AMI patients
3.2.1. Hs‐CRP levels at 1 month post‐AMI
Among TRIUMPH patients with available baseline and 1‐month hs‐CRP (n = 801), 753 (94%) of patients had hs‐CRP ≥2 at baseline, of whom 427 (56.7%) still had hs‐CRP ≥2 at 1 month (Figure 2).
Figure 2.
Patterns of hs‐CRP levels at baseline, 30 days, and 6 months post‐AMI (TRIUMPH only). Levels of hs‐CRP presented as percent for patients with available baseline and 30 days levels (n = 801) (left column) and for patients with available baseline and 6 months levels (n = 434) (right column), stratified by baseline and follow‐up hs‐CRP levels (using 2.0 mg/L as a cutoff point). Abbreviations: AMI, acute myocardial infarction; hs‐CRP, high‐sensitivity C‐reactive protein; TRIUMPH, Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health Status
3.2.2. Hs‐CRP levels at 6 month post‐AMI
Among 434 patients with available baseline and 6‐month hs‐CRP, 407 (93.8%) had elevated hs‐CRP at baseline, and 195 (48%) still had elevated hs‐CRP at 6 months.
3.2.3. Hs‐CRP levels at 1 and 6 months post‐AMI
Out of 354 patients with available 1‐ and 6‐month hs‐CRP, there were 247 (70%) patients with persistent elevation of hs‐CRP at both 1 and 6 months.
3.3. Predictors of hs‐CRP elevation at 30 days post‐AMI
From both TRIUMPH and VIRGO, patients with elevated hs‐CRP levels at 30 days were more likely to be older (per 5 years) (risk ratio [RR]: 1.02, 95% confidence interval [CI]: 1.01‐1.03, P < 0.001), female (RR: 1.11, 95% CI: 1.05‐1.18, P < 0.001), with financial difficulties (RR: 1.16, 95% CI: 1.08‐1.25, P < 0.001), with more comorbidities (history of diabetes [RR: 1.12, 95% CI: 1.06‐1.18, P < 0.001]; hypertension [RR: 1.11, 95% CI: 1.04‐1.18, P < 0.001], smoking [RR: 1.29, 95% CI: 1.21‐1.38, P < 0.001], and obesity [RR: 1.12, 95% CI: 1.10‐1.14, P < 0.001]), and with higher LDL‐C levels (RR: 1.01, 95% CI: 1.008‐1.01, P < 0.001) (Table 2).
Table 2.
Predictors of elevated hs‐CRP at 30 days, using ≥2.0 mg/L as a cutoff point (TRIUMPH and VIRGO pooled analysis)
| RR (95% CI) | P Value | |
|---|---|---|
| Age, per 5 years | 1.02 (1.01‐1.03) | <0.001 |
| Female | 1.11 (1.05‐1.18) | <0.001 |
| BMI, per 5 kg/m2 | 1.12 (1.10‐1.14) | <0.001 |
| Self‐reported financial difficulties (not enough money at end of month) | 1.16 (1.08‐1.25) | <0.001 |
| Self‐reported financial difficulties (just enough money at end of month) | 1.13 (1.05‐1.22) | <0.001 |
| LDL‐C, per 10 mg/dL | 1.01 (1.008‐1.01) | <0.001 |
| History of diabetes | 1.12 (1.06‐1.18) | <0.001 |
| History of hypertension | 1.11 (1.04‐1.18) | <0.001 |
| Smoking, current or active | 1.29 (1.21‐1.38) | <0.001 |
Abbreviations: BMI, body mass index; CI, confidence interval; LDL‐C, low‐density lipoprotein cholesterol; NSTEMI, non–ST‐elevation myocardial infarction; RR, risk ratio; STEMI, ST‐elevation myocardial infarction; TRIUMPH, Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health Status; VIRGO, Variation in Recovery Role of Gender on Outcomes of Young AMI Patients.
The full model included all of the following variables: age, sex, race, financial status, BMI, admission with NSTEMI vs STEMI, in‐hospital revascularization procedure, cardiac comorbidities (history of diabetes mellitus, hypertension, hyperlipidemia, peripheral vascular disease, heart failure, atrial fibrillation, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, and smoking), history of cerebrovascular accident, history of lung disease, alcohol use, left ventricular ejection fraction, creatinine, low‐density lipoprotein levels, and use of a statin medication.
When considering baseline hs‐CRP in the model using TRIUMPH data, hs‐CRP at baseline (per 1 mg/L) was strongly associated with elevated hs‐CRP at 30 days (RR: 1.003, 95% CI: 1.002‐1.003, P < 0.001) (Table 3). Of note, when adding baseline hs‐CRP to the model, female sex, LDL‐C levels, history of diabetes, hypertension and smoking were no longer independently associated with elevated hs‐CRP at 30 days. In a sensitivity analysis using a definition of elevated hs‐CRP to be ≥3.0 mg/L, no significant change was seen in the predictors as compared with an elevated hs‐CRP definition of ≥2.0 mg/L (see Supporting Table 3 in the online version of this article).
Table 3.
Predictors of elevated hs‐CRP at 30 days while adjusting for baseline hs‐CRP, using ≥2.0 mg/L as a cutoff point (TRIUMPH only)
| RR (95% CI) | P Value | |
|---|---|---|
| hs‐CRP at baseline, per 1 mg/L | 1.003 (1.002‐1.003) | <0.001 |
| Age, per 5 years | 1.03 (1.00‐1.06) | 0.019 |
| Female | 1.07 (0.95‐1.21) | 0.211 |
| BMI, per 5 kg/m2 | 1.08 (1.04‐1.13) | <0.001 |
| Self‐reported financial difficulties (not enough money at end of month) | 1.17 (1.00‐1.37) | 0.047 |
| Self‐reported financial difficulties (just enough money at end of month) | 1.21 (1.01‐1.44) | 0.031 |
| LDL‐C, per 10 mg/dL | 1.01 (0.99‐1.02) | 0.101 |
| History of diabetes | 1.07 (0.94‐1.21) | 0.289 |
| History of hypertension | 1.09 (0.96‐1.50) | 0.241 |
| Smoking, current or active | 1.20 (0.95‐1.21) | 0.093 |
Abbreviations: BMI, body mass index; CI, confidence interval; hs‐CRP, high‐sensitivity C‐reactive protein; LDL‐C, low‐density lipoprotein cholesterol; NSTEMI, non–ST‐elevation myocardial infarction; STEMI, ST‐elevation myocardial infarction; TRIUMPH, Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients' Health Status.
The full model included all of the following variables: age, sex, race, financial status, body mass index, admission with NSTEMI vs STEMI, in‐hospital revascularization procedure, cardiac comorbidities (history of diabetes mellitus, hypertension, hyperlipidemia, peripheral vascular disease, heart failure, atrial fibrillation, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, and smoking), history of cerebrovascular accident, history of lung disease, alcohol use, left ventricular ejection fraction, creatinine, low‐density lipoprotein levels, and use of a statin medication.
3.4. Predictors of hs‐CRP elevation at 6 months post‐AMI
From TRIUMPH only, after adjusting for baseline hs‐CRP, being obese, having financial difficulties, a history of hypertension, peripheral vascular disease, and smoking, and having higher baseline hs‐CRP levels were independently associated with elevated hs‐CRP levels at 6 months (see Supporting Table 4 in the online version of this article). Similar results were seen with a definition of elevated hs‐CRP of ≥3.0 mg/L (see Supporting Table 5 in the online version of this article).
3.5. Predictors of persistent hs‐CRP elevation at 1 and 6 months post‐AMI
From TRIUMPH only, while adjusting for baseline hs‐CRP, obesity, reporting financial difficulties, a history of myocardial infarction and higher baseline hs‐CRP levels were independently associated with persistent hs‐CRP elevation (elevated hs‐CRP at both 1 and 6 months) (see Supporting Table 6 in the online version of this article).
4. DISCUSSION
In 2 large real‐world, AMI studies involving 4340 patients recovering from an AMI, we found that hs‐CRP was elevated ≥2.0 mg/L in 59% of patients at 30 days after AMI, 48% of whom had persistent elevations at 6 months. Elevated hs‐CRP levels at follow‐up were observed despite more than 90% of patients being on statin therapy at discharge. Baseline hs‐CRP level was found to be the strongest predictor of 1‐ and 6‐month hs‐CRP levels. Other factors such as older age, female gender, obesity, type 2 diabetes, hypertension, smoking, reporting financial difficulties, and higher LDL‐C on admission also predicted elevated hsCRP at follow‐up. When hs‐CRP levels at baseline were included in the predictive models, only age, obesity, and financial difficulties remained significantly associated with elevated 30‐day hs‐CRP levels.
Our findings extend prior work in the field. Several studies have shown the association of elevated hs‐CRP and worse cardiovascular outcomes in both those with and those at elevated risk for ischemic heart disease.18, 19, 20, 21 The reduction of hs‐CRP with statin therapy in the JUPITER trial demonstrated improved cardiovascular outcomes in individuals without established coronary heart disease.3 Using National Health and Nutrition Examination Survey data, Michos and Blumenthal showed that approximately 6.5 million adults are potentially eligible for statin therapy using JUPITER criteria.22 However, we found that statin therapy after AMI was not a predictor of hs‐CRP levels at follow‐up in patients post‐AMI. This finding may be due to the high use of statin therapy and the high risk of these individuals recovering from an AMI. Furthermore, it is known that elevated hs‐CRP at the time of, and after, an AMI is associated with the occurrence of heart failure,23 early mechanical complications,24 and thrombus formation.25 Moreover, Bohula et al. have demonstrated in the IMPROVE‐IT trial population that after AMI, those with elevated hs‐CRP levels who achieved hs‐CRP level < 2 mg/L had improved long‐term cardiovascular outcomes compared with those with a higher hs‐CRP level.4 Coupled with our insights about the prevalence of elevated hs‐CRP after AMI, these data suggest that screening and treating such patients has the potential to improve their outcomes.
This study provides detailed information on the distribution of hs‐CRP levels after an AMI and patient characteristics associated with hs‐CRP elevation after an AMI that can inform future research and clinical practice. It has been suggested that hs‐CRP levels return to baseline in about 12 weeks after AMI25; however, our data show that 48% of patients with elevated hs‐CRP at the time of their AMI had persistent elevations at 6 months post‐AMI. These findings are paramount in understanding the ongoing inflammatory risk for patients post‐AMI.26 Our data may have important implications in describing the proportion of patients potentially eligible for targeted anti‐inflammatory treatment strategies, such as low‐dose methotrexate or canakinumab, beyond statin therapy alone.
We found that several patient characteristics were associated with elevated hs‐CRP levels after AMI. Female sex was associated with elevated hs‐CRP levels, which is consistent with prior literature.27 Moreover, older age and other comorbidities, including obesity, diabetes, hypertension, smoking, and higher LDL‐C levels were also independently associated with elevated hs‐CRP in this study. Although some may consider it worthwhile to screen all patients after discharge, those with more risk factors may be particularly high‐yield targets for such screening. It remains unproven whether routine assessment and further reduction of hs‐CRP after AMI is associated with cardiovascular benefit, although several ongoing studies are examining these benefits.14, 28
Our study findings should be interpreted in light of the following potential limitations. First, hs‐CRP levels were only collected in a subset of patients in both registries, which could introduce bias. However, there is no a priori reason to expect that willingness to participate in blood collection would be associated with hs‐CRP levels. Second, the 2 registries included different patient populations, with VIRGO focusing on young females. To overcome the differences in selection processes for the 2 registries, we adjusted for study (TRIUMPH or VIRGO) in our hierarchical models. On the other hand, given the similarities in study design and data collection, we believe that combining the 2 registries increased our power and breadth of patients. Third, hs‐CRP is a general acute‐phase reactant that could be elevated due to numerous noncardiac reasons. Unfortunately, noncardiac causes for hs‐CRP elevations, such as autoimmune and infectious diseases, were not available in the data. Although the prevalence of autoimmune disease in the general population is only about 3%, it may have been an additional risk factor, had the presence of these diseases been collected.29 Finally, these studies were conducted a decade ago, although there is no reason to suspect that the prevalence of elevated hs‐CRP or the relationship between patient characteristics and elevated hs‐CRP would have changed over this time period.
5. CONCLUSION
We found that 59% of patients had elevated hs‐CRP levels 30 days after AMI and that it continued to be elevated at 6 months in 70% of patients. Patients with elevated hs‐CRP levels at 30 days were more likely to be older, female, with higher BMI, with financial difficulties, black, and to have more comorbidities (diabetes, hypertension, and smoking) and higher LDL‐C levels. Moreover, hs‐CRP level at the time of an AMI was highly associated with elevated hs‐CRP at follow‐up after AMI. Given the high prevalence of elevated hs‐CRP 30 days after discharge, further studies to test routine screening after AMI may be warranted to identify higher‐risk patients for more aggressive secondary prevention.
Supporting information
Table S1. Patients' characteristics of those with vs without hs‐CRP levels at 30 days.
Table S2. Patient characteristics by Registry in patients that had 1 month hs‐CRP levels
Table S3. Predictors of hs‐CRP elevation 30 days, using ≥3.0 mg/L as a cutoff point (TRIUMPH and VIRGO polled analysis).
Table S4. Predictors of elevated hs‐CRP at 6 months while adjusting for baseline hs‐CRP, using ≥2.0 mg/L as a cutoff point (TRIUMPH only).
Table S5. Predictors of hs‐CRP elevation 6 months while adjusting for baseline hs‐CRP, using ≥3.0 mg/L as a cutoff point (TRIUMPH only).
Table S6. Predictors of persistent hs‐CRP elevation at 1&6 months while adjusting for baseline hs‐CRP, using ≥2.0 mg/L as a cutoff point (TRIUMPH only).
Qintar M, Sharma PP, Pokharel Y, et al. Prevalence and predictors of elevated high‐sensitivity C‐reactive protein in post–myocardial infarction patients: Insights from the VIRGO and TRIUMPH registries. Clin Cardiol. 2017;40:1205–1211. 10.1002/clc.22816
Dr. Sharma is an employee of Novartis. Dr. Spertus received grant funding from Patient‐Centered Outcomes Research Institute, Abbott Vascular, Lilly, and an equity interest in Health Outcomes Sciences (copyright to the Seattle Angina Questionnaire (SAQ)). The remaining authors have no relevant relationships to disclose.
Funding information Drs. Qintar and Pokharel are supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number T32HL110837. TRIUMPH was funded by the National Heart, Lung, and Blood Institute (grant number P50 HL077113) and CV Outcomes, Kansas City, Missouri. The VIRGO study was supported by the National Heart, Lung, and Blood Institute (grant number 5R01HL081153). A supplemental grant for additional analyses was provided by Novartis. All data collection, data analyses, the preparation of the manuscript, and the decision to submit the manuscript for publication were done independently of the study sponsors.
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Associated Data
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Supplementary Materials
Table S1. Patients' characteristics of those with vs without hs‐CRP levels at 30 days.
Table S2. Patient characteristics by Registry in patients that had 1 month hs‐CRP levels
Table S3. Predictors of hs‐CRP elevation 30 days, using ≥3.0 mg/L as a cutoff point (TRIUMPH and VIRGO polled analysis).
Table S4. Predictors of elevated hs‐CRP at 6 months while adjusting for baseline hs‐CRP, using ≥2.0 mg/L as a cutoff point (TRIUMPH only).
Table S5. Predictors of hs‐CRP elevation 6 months while adjusting for baseline hs‐CRP, using ≥3.0 mg/L as a cutoff point (TRIUMPH only).
Table S6. Predictors of persistent hs‐CRP elevation at 1&6 months while adjusting for baseline hs‐CRP, using ≥2.0 mg/L as a cutoff point (TRIUMPH only).