C-reactive protein in cardiovascular disease

INTRODUCTION — Atherosclerotic cardiovascular disease (ASCVD) is common in the general population and is the most common cause of death in the United States as well as in most developed countries. ASCVD can be subdivided into four major areas:

●Coronary heart disease manifesting as myocardial infarction, angina pectoris, congestive heart failure, and sudden cardiac death

●Cerebrovascular disease manifesting as stroke and transient ischemic attack

●Peripheral artery disease manifesting as intermittent claudication and critical limb ischemia

●Aortic atherosclerosis and thoracic or abdominal aortic aneurysm

Inflammation is a known factor in the development of atherosclerosis and subsequent ASCVD events. Ongoing inflammation increases the vulnerability of an atherosclerotic lesion to erosion or rupture. The most extensively studied biomarker of inflammation in ASCVD is C-reactive protein (CRP), an acute phase protein that is produced predominantly by hepatocytes under the influence of cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha [1]. (See "Acute phase reactants".)

Despite a lack of specificity for the cause of inflammation, data from numerous epidemiologic studies have shown a significant association between elevated serum or plasma concentrations of CRP and the prevalence of underlying atherosclerosis, the risk of recurrent cardiovascular events among patients with established disease, and the incidence of first cardiovascular events among individuals at risk for atherosclerosis [2,3]. These issues as well as the mechanisms of association with cardiovascular risk will be reviewed here, along with the role of serum CRP in screening for ASCVD risk. The incremental value of CRP beyond traditional risk factors for estimating ASCVD risk in an individual patient is debated and is discussed separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

POSSIBLE PATHOGENIC ROLE OF CRP — The participation of inflammatory cells and mediators in atherothrombosis is well established [4]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)

Whether serum CRP is a nonspecific marker that is increased as part of the acute phase response to inflammatory stimuli or a direct participant in the progression of atherosclerosis and its clinical consequences has been widely discussed, and the evidence has mounted that it is not causal [5-7]. Early observations suggested that there may be a direct effect of CRP on the development of atherosclerosis [8-12].

However, other reports have not supported a direct role of CRP in atherogenesis [3,10,13-19]. Observations from two large (Mendelian randomization) studies suggest that there is not a direct pathogenic role of CRP:

●In a study of over 50,000 individuals with and without ischemic ASCVD in whom the levels of high-sensitivity CRP and genotype for four CRP polymorphisms were known, the following findings were noted [3]:

•The risk of ischemic heart disease was increased significantly in persons who had serum CRP levels above 3 mg/L, as compared with persons with CRP levels below 1 mg/L (adjusted hazard ratio 1.6, 95% CI 1.2-2.1). (See 'Known stable coronary disease' below.)

•Genotype combinations of the four CRP polymorphisms explained a difference in plasma CRP levels of up to 64 percent, resulting in a theoretically predicted increased risk for ischemic heart and cerebrovascular disease of as much as 32 and 25 percent, respectively.

•Despite the theoretical considerations, none of the genotype combinations were associated with an increased risk of ischemic ASCVD.

●Similar findings were noted in a second report of similar design, which used both genome-wide association study and Mendelian randomization techniques [19]. Polymorphisms in five genetic loci strongly associated with CRP levels were identified. However, variants in these CRP loci were not associated with the incidence of coronary heart disease in an analysis of over 28,000 cases and 100,000 controls.

CRP ASSAYS

Test characteristics — CRP can be measured using various assays with different testing characteristics. The assays, however, are broadly separated into traditional assays and high sensitivity CRP (hs-CRP) assays [20]. It is the hs-CRP assays that are used to determine cardiovascular risk.

●Traditional assays, developed to aid in the diagnosis of infectious or inflammatory illnesses, have a limit of detection in the range of 3 to 5 mg/L. While generally helpful for the diagnosis of acute infective or inflammatory episodes, this range is above the concentration observed in most apparently healthy individuals, thereby limiting its discriminatory ability to screen for ASCVD.

●hs-CRP assays detect concentrations of CRP down to 0.3 mg/L and below [20,21]. These hs-CRP assays are the assays used to assess cardiovascular risk because they are able to quantitate CRP within the range normally seen in asymptomatic patients (<3 mg/L).

While the ideal value that constitutes a high serum hs-CRP (and increased cardiovascular risk) is not clearly defined, ranges articulated by the Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA) for the use of serum hs-CRP to estimate cardiovascular risk are routinely employed when hs-CRP is measured for this purpose [2]:

●Low-, average-, and high-risk values can be defined as <1, 1 to 3, and >3 mg/L; these values correspond to approximate tertiles in the general population. A value above 10 mg/L should initiate a search for a source of infection or inflammation. This value should then be repeated in two weeks to determine if the elevation is sustained.

●Due to the variability of values in an individual over time, the average of two measurements, fasting or nonfasting, and optimally obtained two weeks apart, provides a more stable estimate of cardiovascular risk than a single measurement. (See 'Variability within an individual patient' below.)

●The population distribution of hs-CRP may vary by race and ethnicity; however, these differences are likely explained mostly by the prevalence of other risk factors that are associated with hs-CRP [22,23]. As such, the same cutoff values are used across most populations. (See 'Is CRP an independent risk indicator?' below.)

We incorporate these guidelines into our approach to the use of CRP assays in determining cardiovascular risk. (See 'Our approach to screening with CRP' below.)

Clinical context — As with any diagnostic test, hs-CRP must be evaluated within the specific clinical context of an individual patient. Of particular interest are comorbid illnesses and medications that may influence CRP levels, such as the use of menopausal hormone therapy in women.

Definition of normal — There is no standardized CRP value that can be considered normal. However, individuals with values <1 mg/L have been considered to be at lowest risk [24].

Variability within an individual patient — hs-CRP values fluctuate in an individual over time [25,26]. These fluctuations are thought to reflect changes in an individual's systemic inflammatory status. As such, if using hs-CRP for cardiovascular risk assessment, the CDC/AHA recommends that the hs-CRP be checked twice to confirm a stable value prior to integrating for risk assessment. The following observations illustrate the magnitude of variability of CRP in adults:

●In a study of 113 healthy adults, the variability in quarterly serum CRP measurements over one year was similar to that for serum total cholesterol [25]. Between the first and second measurements, 63 percent of hs-CRP values remained in the same quartile, with 90 percent remaining within one quartile of the baseline value.

●In a study of 259 women aged 18 to 44 years in whom CRP levels were measured up to eight times throughout their menstrual cycles, significant variation of CRP levels was noted throughout the cycle, with CRP levels being highest during menses and lowest during ovulation [27].

●A greater degree of variability was noted in a study in which serial measurements of serum CRP were obtained in 159 patients with stable ischemic heart disease [26]. When patients were stratified into three risk categories (CRP <1, 1 to 3, and >3 mg/L), 40 percent of patients changed risk category between the first and second measurements. Similar fluctuations were noted in interleukin (IL)-6, another inflammatory marker. Significant within-subject variation in hs-CRP levels measured an average of 19 days apart has also been reported among a cohort of 541 apparently healthy persons, with approximately one-third of those with an elevated hs-CRP level (>10 mg/L) reclassified within the normal range on repeat testing [28].

These observations are consistent with the hypothesis that dynamic systemic inflammatory status may affect coronary risk. They also point to a potential limitation of using serial measurements of CRP to monitor risk status or the response to medical therapies.

Gender differences — Although women have higher levels of CRP than men both in the general population and in patients with stable angina [22,29], elevated serum CRP predicts ASCVD in women (figure 1) as well as men [30-36].

Variability within ethnic groups — The interpretation of CRP concentration should be in the context of the ethnicity of the patient, since ethnic background appears to have some influence on baseline CRP levels [37-39]. In a systematic review and meta-analysis of 221,287 individuals from 89 studies, the geometric mean of hs-CRP levels varied significantly depending on ethnic background [37]:

●2.6 mg/L in Black subjects (n = 18,585)

●2.5 mg/L in Hispanic subjects (n = 5049)

●2.3 mg/L in South Asian subjects (n = 1053)

●2.0 mg/L in non-Hispanic White subjects (n = 104,949)

●1.0 mg/L in East Asian subjects (n = 39,521)

In the Strong Heart Study (a high-risk population of 3277 Native Americans without ASCVD at the time of enrollment but with a 50 percent prevalence of diabetes), the median serum CRP was 3.2 mg/L, higher than that noted in many other populations [38]. After adjusting for traditional risk factors, CRP remained an independent predictor for future ASCVD in most subgroups. However, CRP was not an incremental predictor of risk in the diabetic patient subgroup [38].

Specificity — CRP is an acute phase reactant that arises with most inflammatory disorders, thereby reducing its specificity for prediction of ASCVD risk. Thus, elevated values must be considered in the context of other medical conditions. Levels greater than 10 mg/L are likely to be due to systemic inflammatory states such as major infection, trauma, or chronic inflammatory disease [2,20]. (See "Acute phase reactants".)

Comorbid illness — The effect of comorbid illnesses on the reliability of hs-CRP as a risk marker for ASCVD is largely unknown. As examples, inflammatory diseases such as rheumatoid arthritis or systemic lupus erythematosus would be expected to result in higher circulating CRP levels, while cirrhotic liver disease may blunt the production of CRP, leading to lower circulating levels [40]. There are no published studies evaluating the effect of comorbid inflammatory illnesses or liver disease on the discriminatory power of CRP in ASCVD risk stratification.

Renal dysfunction — The predictive value of serum CRP applies to patients with end-stage kidney disease on maintenance hemodialysis. (See "Risk factors and epidemiology of coronary heart disease in end-stage kidney disease (dialysis)".)

●Among a cohort of 280 patients on chronic hemodialysis, an elevated serum CRP (>8 mg/dL) was seen in nearly one-half (46 percent) of patients and was significantly related to cardiovascular mortality [41].

●Among a cohort of 173 patients on chronic hemodialysis, only 58 patients had no history of coronary heart disease (CHD) or CHD equivalent [42]. Over a 27-month follow-up of the patients without CHD or CHD equivalent, mortality was significantly higher among those with CRP ≥3 mg/L compared with CRP <3 mg/L (50 versus 18 percent).

ASSOCIATION OF CRP WITH CARDIOVASCULAR RISK — Data from numerous epidemiologic studies have shown a significant association between elevated serum or plasma concentrations of CRP and the prevalence of underlying atherosclerotic vascular disease, the risk of recurrent cardiovascular events among patients with established disease, and the incidence of first cardiovascular events among individuals not known to have atherosclerosis. When considered alone or in combination with traditional cardiovascular risk factors, elevated CRP levels have been associated with a higher risk of future cardiovascular events [43-46].

General population without known ASCVD — Several large population-based studies evaluating CRP in unselected asymptomatic populations have shown that, among apparently healthy individuals, the baseline level of CRP is associated with the long-term risk of a first myocardial infarction (MI), ischemic stroke, hypertension, peripheral vascular disease, sudden cardiac death, and all-cause mortality (figure 2) [30,44,47-54]. The correlation between CRP and cardiovascular risk persists after adjustment for age, smoking, lipid levels, blood pressure, and diabetes [20,24,30-34,47,50,55,56].

Population at high risk for or with known ASCVD

CRP after statin treatment and cardiovascular disease — In over 31,000 patients from three clinical trials of statin therapy, residual (or “after-treatment”) high-sensitivity CRP had a greater predictive value for cardiovascular events and death than residual (“after-treatment”) LDL-C [57]. Specific findings are described as follows:

●Residual inflammatory risk was associated with incident major adverse cardiovascular events (highest versus lowest high-sensitivity CRP quartile; hazard ratio [HR] 1.31; 95% CI 1.20-1.43), cardiovascular mortality (HR 2.68; 95% CI 2.22-3.23), and all-cause mortality (HR 2.42; 95% CI 2.12-2.77.

●Residual LDL-C was not associated with major adverse cardiovascular events but was associated with higher cardiovascular mortality (HR 1.27; 95% CI 1.07-1.50) and all-cause mortality (HR 1.16; 95% CI 1.03-1.32).

Is CRP an independent risk indicator? — While serum CRP does appear to act as an independent predictor of ASCVD in the general population, the predictive value added to that determined by screening for other coronary risk factors is small [58]. Instead, serum CRP appears to add the greatest predictive value in a subset of patients with intermediate coronary heart disease (CHD) risk as determined by other measures such as the Framingham Risk Score (calculator 1 and calculator 2).

Several large studies have demonstrated that serum CRP adds incremental information to global risk assessment using traditional cardiovascular risk factors [24,59-61].

●In the largest case-control study, 2459 patients with a history of MI or death from CHD were compared with 3969 controls without a history of CHD within a cohort study of almost 19,000 patients in Iceland [59]. At a mean follow-up of 18 years, when compared with patients with CRP values in the bottom third (<0.78 mg/L), patients with serum CRP in the top third (>2.0 mg/L) had a significantly higher risk of developing CHD (odds ratio [OR] 1.92). However, the magnitude of this effect decreased after adjustment for age, sex, established coronary risk factors, and year of recruitment (OR 1.45). The predictive value of serum CRP in this report remained independent of established risk factors but, in contrast to previous studies, was weaker than that of total cholesterol, smoking history, or systolic blood pressure.

●The Framingham Offspring Study evaluated CRP levels in 3006 patients without ASCVD and followed these patients for an average of 12 years. When compared with patients with CRP <1 mg/L, and after adjusting for traditional risk factors, patients with CRP >3 mg/L had a significantly higher risk of hard CHD events including MI or CHD-related death (hazard ratio [HR] 1.88, 95% CI 1.18-3.00) as well as a higher risk of total ASCVD (CHD, stroke, transient ischemic attack, claudication; HR 1.58, 95% CI 1.16-2.15) [24].

In addition, several meta-analyses have found a significant relationship between baseline CRP and subsequent CHD or cardiovascular events [59,62,63]. The largest and most recent of these, a 2012 meta-analysis from the Emerging Risk Factors Collaboration, which evaluated 246,669 persons without prior ASCVD who were pooled from 52 prospective studies, showed that the addition of CRP level to traditional risk factors modestly improved the risk assessment, with a small but significant net reclassification improvement (1.5 percent) [64].

In contrast to these findings, other observational studies have suggested only a small or no incremental contribution of serum CRP to traditional risk factors [65-67]:

●In a review of over 15,000 individuals from the third National Health and Nutrition Examination Survey (NHANES) in the United States, high serum CRP (>3 mg/L) was rare in the absence of any borderline or abnormal coronary risk factor (4.4 percent in men and 10.3 percent in women) [65]. The likelihood of a high serum CRP was largely attributable to the presence of other risk factors (78 percent in men and 67 percent in women). It was concluded that serum CRP may have limited clinical utility as a screening tool beyond other known cardiovascular risk factors.

●Similar findings were noted in the ARIC study, which assessed the association of 19 novel risk markers, including serum CRP, with incident CHD in nearly 16,000 adults followed for up to 15 years [66]. The CRP level did not add significantly to the basic risk factor model (age, sex, total and high-density lipoprotein cholesterol levels, systolic blood pressure, antihypertensive medication use, smoking status, and diabetes) as assessed by the change in area under receiver operating characteristic curves.

Known stable coronary disease — Among patients with known stable coronary disease, a strong positive correlation between CRP measured at baseline and future acute coronary events has been demonstrated in most studies [68-74]. However, results from these studies cannot be directly compared as cut points for CRP levels differed from study to study.

In an evaluation of 3771 patients with stable coronary artery disease (CAD) in the PEACE trial, in which patients had high sensitivity CRP (hs-CRP) measured at baseline (with categorization of low, average, or high risk, using cut points of <1, 1 to 3, and >3 mg/L, respectively) and were followed for outcomes of cardiovascular death, MI, or stroke over a mean follow-up of 4.8 years, the following findings were noted [75]:

●Across all measured subgroups, including men and women, patients on or off statin therapy, and patients with or without prior coronary revascularization, higher baseline hs-CRP levels were associated with a significantly higher rate of cardiovascular events compared with those with hs-CRP <1 mg/L (hs-CRP 1 to 3 mg/L: adjusted HR 1.4, 95% CI 1.1-1.8; hs-CRP >3 mg/L: adjusted HR 1.5, 95% CI 1.2-2.0).

●An elevated hs-CRP was predictive of the development of heart failure (HF) and new diabetes.

In addition to the association with cardiovascular outcomes among patients with stable coronary disease, serum CRP may predict coronary disease progression [76].

Acute coronary syndromes — The elevated levels of acute phase reactants in patients with an acute coronary syndrome (ACS) appear to be a marker of widespread underlying vascular inflammation and hyperresponsiveness of the inflammatory system to even small stimuli [77]. The association between ACS and elevated serum concentrations of acute phase reactants, such as CRP [71,78-80], serum amyloid A (SAA) [79,80], and interleukin (IL)-6 [81], suggests that chronic inflammation of the coronary arterial wall plays an important role in plaque instability and ACS. However, elevated CRP levels (and other inflammatory markers) are not the result of localized plaque disruption alone. As such, CRP levels should not be used as a diagnostic test to rule in or exclude ACS [82]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)

The following observations from several studies are consistent with this hypothesis:

Prognosis after ACS — Increased CRP concentrations at admission and prior to hospital discharge are a marker for a worse short- and long-term prognosis in patients with a non-ST elevation ACS [79,83-88]. Some but not all studies have found that serum CRP predicts the risk of a recurrent in-hospital cardiac event [71] or 30-day or long-term mortality after an ST elevation ACS [89-93]. Elevations in serum CRP early after ACS may reflect the extent of and reaction to myocardial injury. Accordingly, if serum CRP is to be used for long-term cardiovascular assessment, the measurement should be delayed for at least four to six weeks after an MI to permit resolution of the acute phase reaction [94]. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes" and "Risk factors for adverse outcomes after ST-elevation myocardial infarction".)

In the PROVE IT-TIMI 22 trial, among 4162 patients stabilized after ACS, those with hs-CRP >2.0 mg/L were at a nearly twofold higher risk of developing new or worsening HF during a mean follow-up of 24 months [95]. (See 'Other cardiovascular conditions' below.)

Elevated periprocedural CRP levels are also predictive of a worse outcome after elective or urgent coronary artery stenting, which itself can elicit an inflammatory response [96-101]. As an example, among 2849 patients who received a drug-eluting stent for symptomatic CHD (stable angina or non-ST elevation ACS) and were followed for an average of 2.2 years, patients with an elevated CRP level (defined as ≥3 mg/L) were significantly more likely to experience death, nonfatal MI, stroke, or stent thrombosis (5.6 versus 1.7 percent in those with CRP level <3 mg/L; HR 2.8, 95% CI 1.8-4.3) [101]. Among patients with elevated serum CRP prior to stenting, statins appear to reduce the risk of adverse cardiac events. (See 'Statins' below.)

Residual inflammation and prognosis after PCI — Among patients with CAD who have undergone PCI, secondary prevention of future events is the primary goal of therapy.

●The impact of ongoing residual inflammation on future events and mortality was retrospectively assessed in a cohort of 7026 patients who underwent PCI for any indication (53 percent stable angina, 43 percent ACS) at a single center between 2009 and 2016 [102]. Patients had hs-CRP measured at baseline and again at least four weeks later, with hs-CRP >2 mg/L considered high, and were categorized as persistently high risk (hs-CRP >2 mg/L at both time points), increasing risk (low, then high hs-CRP), attenuated risk (high, then low hs-CRP), or persistently low risk (hs-CRP low at both time points). Compared with persistently low-risk patients, patients with persistently high risk had greater than three-fold risk of death after one year (2.6 versus 0.7 percent; adjusted HR 3.2; 95% CI 1.7-6.0) as well as a significantly greater risk of MI (7.5 versus 4.3 percent; adjusted HR 1.6; 95% CI 1.2-2.1).

●In a retrospective review of the prospective randomized EXCEL trial, which compared PCI and CABG for left main coronary stenosis, baseline CRP levels were available in 999 patients [103]. A linear association was seen between increasing CRP levels and the composite primary outcome (death, MI, stroke at three years); patients with CRP ≥10 mg/L had a nearly threefold higher event rate compared to those with CRP <3 mg/L (HR 2.9; 95% CI 1.9-4.5).

While these data raise the potential for therapeutically targeting residual inflammation post-PCI, therapeutic implications have not yet emerged.

Other cardiovascular conditions

●Heart failure – Data have been limited on the predictive value of serum CRP in patients with HF but generally suggest an association between CRP and outcomes [104-106]. This issue is discussed in detail separately. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'C-reactive protein'.)

●Cerebrovascular disease – Similar to its role in atherosclerotic coronary disease, CRP is an independent marker for the development and progression of early carotid atherosclerotic disease (but not the extent of disease) [107], the risk of ischemic stroke [108,109], and prognosis after a stroke [110-112]. In one report, for example, an increase in serum CRP between 12 and 24 hours after symptom onset in patients with a first ischemic stroke predicted an unfavorable outcome [112]. In an observational study of 6430 participants followed for an average of 8.2 years, it was shown that although CRP levels are associated with stroke risk, their use in the assessment of individual stroke risk was limited when other baseline characteristics were taken into account [109].

●Cardiac allograft vasculopathy – CAD following cardiac transplant is the leading cause of death or retransplantation in cardiac transplant recipients surviving more than six months. Elevated serum CRP appears to be a predictor for transplant vasculopathy and allograft failure [113,114]. (See "Heart transplantation in adults: Prognosis" and "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)

●Atrial fibrillation – An inflammatory process may play a role in the genesis of atrial fibrillation (AF), as suggested by the high incidence of AF after cardiac surgery. Whether inflammation plays a direct causal role in the development and perpetuation of AF, or if it is a marker for other conditions that predispose to AF remains to be determined. (See "Atrial fibrillation and flutter after cardiac surgery" and "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Inflammation and infection'.)

●Adult congenital heart disease — Elevated CRP appears to be a marker of increased risk of death, hospitalization, and worse functional status in adults with congenital heart disease. A prospective cohort study followed 707 adult patients with congenital heart disease (mean age 39 years) with initial clinical assessment between 2012 and 2016 for an average of 27 months [115]. Compared with persons with CRP in the lowest three quartiles, those with CRP in the highest quartile (CRP ≥2.98 mg/L) were at significantly higher risk of death (12 versus 2 percent; adjusted HR 4.2; 95% CI 1.9-9.6) or the combined outcome of death or non-elective hospitalization (31 versus 11 percent; adjusted HR 2.0; 95% CI 1.4-3.0). The mechanistic link(s) between CRP and adverse outcome in this population remain to be determined.

OUR APPROACH TO SCREENING WITH CRP — Elevated serum or plasma CRP is an independent predictor of atherosclerosis among apparently healthy men and women. Among apparently healthy men, the plasma concentration of CRP predicts the long-term risk of a first myocardial infarction, ischemic stroke, hypertension, peripheral artery disease, sudden cardiac death, and total mortality.

Our approach — The use of high-sensitivity CRP (hs-CRP) to screen the general population for cardiovascular risk is controversial. While some experts recommend the routine measurement of hs-CRP at the time of cholesterol screening to be used as adjunctive data in the overall assessment of cardiovascular risk, we continue to prioritize the assessment of traditional risk factors and consider hs-CRP primarily for those with intermediate cardiovascular risk as determined using traditional risk factors and one or more of the available risk calculators [20]. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

There are a number of issues that impact upon the utility and cost-effectiveness of this test for routine screening [116,117]:

●What is the appropriate range of "normal" concentrations for serum hs-CRP if one were to target therapy? As noted above, the CDC/AHA statement defined high risk as a value above 3 mg/L [2], and many studies evaluating the predictive value of serum CRP compared patients with serum hs-CRP >2 or 3 mg/L to those with values <1 mg/L [30,34,59,118]. However, additional evidence indicates that patients with serum CRP levels above 1 mg/L may be at increased risk compared with those with lower values [118]. Moreover, the "normal" concentration of CRP appears to vary based on ethnicity and, potentially, gender.

●How does the lack of specificity of hs-CRP for ASCVD influence the interpretation of hs-CRP? (See 'Specificity' above.)

●Should patient management be altered based upon the results of CRP testing? Until the publication of the JUPITER trial, there was no direct evidence that lowering CRP alone would result in a reduction of cardiovascular risk [119]. The JUPITER trial randomly assigned 17,802 healthy men (aged 50 and older) and women (aged 60 and older) with a low density lipoprotein-cholesterol (LDL-C) level below 130 mg/dL (3.4 mmol/L) and a CRP level of at least 2.0 mg/L to treatment with rosuvastatin 20 mg daily or placebo [120,121]. The trial was stopped early for benefit after a median follow-up of 1.9 years. Because the trial did not include a group with low hs-CRP, it is not possible to know whether the demonstrated benefit of rosuvastatin in the trial was specifically related to underlying vascular inflammation manifest by hs-CRP. However, the primary results of the JUPITER trial suggest a benefit to statin therapy among individuals with an LDL-C level below 130 mg/dL and a CRP level of at least 2.0 mg/L.

CRP is an important marker of inflammation, and its measurement using commercially available hs-CRP assays can aid in ASCVD risk stratification. A large body of available evidence guides the treatment of patients with traditional ASCVD risk factors (ie, hypertension, diabetes mellitus, hyperlipidemia, smoking, obesity) using a combination of lifestyle changes and pharmacotherapies. There is a relative paucity of evidence demonstrating improved ASCVD outcomes following the treatment of an elevated CRP level on top of treating traditional ASCVD risk factors. As such, professional guidelines do not recommend the routine use of hs-CRP to screen for ASCVD risk in the general population. However, screening with hs-CRP appears reasonable in selected populations considered at intermediate risk for ASCVD based on clinical risk factors using one or more of the available risk calculators (ie, 10 to 20 percent at 10 years) in whom treatment with a statin would be expected to reduce the risk of future ASCVD events by 25 percent or more. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

For patients at intermediate risk for ASCVD (ie, 10 to 20 percent risk at 10 years) who do not otherwise qualify for lipid-lowering therapy, we suggest a screening measurement of hs-CRP. We take the following approach to the interpretation of these values:

●A value above 10 mg/L should prompt consideration of a source of infection or inflammation, with repeat measurement of hs-CRP in two weeks.

●A value of 3 to 10 mg/L should prompt a discussion regarding overall ASCVD risk, lifestyle modifications, management of risk factors for atherosclerosis, and the possibility of risk reduction therapy using a statin.

●A value of 1 to 3 mg/L should be repeated in two weeks to determine an average value and prompt a discussion regarding lifestyle modifications and the potential for treatment with a statin if the hs-CRP value is 2.0 mg/L or greater.

●A value <1 mg/L suggests a lower risk of future ASCVD events.

Different cutoffs may be required for non-white patients in whom risk related to CRP appears variable based on different baseline values of CRP. (See 'Variability within ethnic groups' above.)

Recommendations of others — Several groups have issued guidelines addressing the role of CRP in screening for coronary heart disease (CHD).

In 2018, the United States Preventive Services Task Force (USPSTF) issued recommendations about the use of nontraditional risk factors in the risk assessment for CHD [122,123]. They concluded with regard to hs-CRP testing that there are insufficient data to assess the balance of benefits and harms of using CRP to screen asymptomatic men and women to prevent CHD events.

In 2009, the Canadian Cardiovascular Society issued guidelines covering the treatment of dyslipidemia and the prevention of ASCVD [124]. Screening hs-CRP was recommended in men older than 50 years and women older than 60 years who were at intermediate risk by the Framingham Risk Score (FRS; 10 to 20 percent at 10 years) and who would otherwise not qualify for lipid-lowering therapy because of an LDL <3.5 mmol/L (135 mg/dL). These individuals were felt to benefit from screening with hs-CRP due to a potential benefit from statin therapy in those with elevated hs-CRP levels [120].

The 2003 CDC/AHA statement on markers of inflammation and CVD included the following conclusions concerning the use of serum hs-CRP measurements in determining cardiovascular risk that remain pertinent to its clinical application [2]:

●If used, hs-CRP should be measured twice, optimally two weeks apart, with the values averaged. Values should be reported in mg/L.

●Low-, intermediate-, and high-risk CRP values were defined as <1, 1 to 3, and >3 mg/L. A value above 10 mg/L should be repeated after an interval of at least two weeks and the patient evaluated for infection or inflammation.

●In patients at intermediate risk for ASCVD (10 to 20 percent at 10 years by the FRS), hs-CRP may help direct further evaluation and therapy for primary prevention, at the discretion of the clinician.

EFFECT OF THERAPY — A number of drugs used in the treatment of ASCVD and certain dietary modifications reduce serum CRP. It is therefore possible that reduced inflammation contributes to the beneficial effects of these medications.

Statins

Effect on CRP — Multiple statins significantly decrease serum CRP in patients with hyperlipidemia; this decrease appears to be independent of reductions in low density lipoprotein-cholesterol (LDL-C) [125-128]. The effect of statins on CRP may be mediated in part by reduced monocyte expression of interleukin (IL)-6 and tumor necrosis factor-alpha [129,130] or by direct suppression of CRP gene transcription [131].

Therapy with a statin reduces serum CRP both after an acute coronary syndrome (ACS) [73,127,132,133] and when given for primary prevention [128,134]. The fall in serum CRP is seen as early as 14 days [126]. In a literature review of 13 controlled trials, statins reduced CRP levels by 13 to 50 percent compared with placebo; there was no advantage of one statin over another in five studies making direct comparisons [132]. In phase Z of the A to Z trial, more intensive statin therapy was associated with a modestly greater reduction in CRP [132].

Reduction in coronary risk — The observations that statin therapy reduces serum CRP and that serum CRP is correlated with cardiovascular risk raise the possibility that the risk reduction with statin therapy may be attributed, at least in part, to anti-inflammatory effects. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)

Several clinical studies have provided supportive evidence for this concept:

●In patients undergoing percutaneous coronary intervention, observational studies suggest that benefit from statin therapy is principally seen in those with a serum CRP in the upper 25 to 50 percent of the study population [135,136].

●In the AFCAPS/TexCAPS trial of primary prevention, lovastatin reduced CRP by almost 15 percent [134]. A significant reduction in coronary events was seen, not only in patients with an elevated total cholesterol-to-HDL cholesterol ratio, but also in those with an elevated serum CRP but no elevation in lipid ratio. Modeling of the AFCAPS/TexCAPS data suggested that 58-year-old men or women with a serum LDL-C concentration below 149 mg/dL (3.9 mmol/L) might benefit from statin therapy if they have a serum CRP concentration ≥1.6 mg/L [137].

●In Phase Z of the A to Z trial, 4497 patients with an ACS were randomly assigned to aggressive statin therapy (simvastatin 40 mg/day for one month, then 80 mg/day) or to delayed conservative statin therapy (placebo for four months, then simvastatin 20 mg/day) [132]. At one month, patients in the aggressive therapy arm had a marked reduction in LDL-C concentration, but no reduction in the incidence of the primary end point (cardiovascular death, myocardial infarction [MI], readmission for ACS, or stroke). Instead, the benefit seen in Phase Z corresponded to the timing of a reduction in serum CRP seen when the dose of simvastatin was increased from 40 to 80 mg/day. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Further assessment of patients in Phase Z of the A to Z trial showed that levels of high sensitivity CRP (hs-CRP) at 30 days and four months after ACS were independently associated with long-term survival. This study also showed that patients treated with more aggressive statin therapy are more likely to achieve lower levels of hs-CRP [138].

Patients with hs-CRP >3 mg/L at 30 days had significantly higher two-year mortality rates than those with hs-CRP 1 to 3 mg/L or hs-CRP <1 mg/L (6.1 versus 3.7 versus 1.6 percent), and results were similar with hs-CRP measured at four months. Patients allocated to early intensive statin therapy were significantly more likely to achieve hs-CRP levels <1 mg/L at 30 days and four months.

●In the PROVE IT-TIMI 22 trial, 4162 patients with an ACS were randomly assigned to atorvastatin 80 mg/day or pravastatin 40 mg/day [133]. There were significant reductions in serum CRP by 30 days in both treatment arms. There was only a limited correlation between the achieved levels of CRP and the achieved levels of LDL-C; less than 3 percent of the variance in achieved serum CRP was explained by the variance in achieved LDL-C. Despite the nearly complete independence of these two factors, there was also a linear relationship between the levels of CRP achieved after statin therapy and the risk of recurrent MI or coronary death. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

●The JUPITER trial, which randomly assigned patients with an LDL-C level below 130 mg/dL (3.4 mmol/L) and a CRP level of at least 2.0 mg/L to treatment with rosuvastatin 20 mg daily or placebo and demonstrated better outcomes in the treated group, is discussed elsewhere. (See 'Our approach' above.)

In the aggregate, these studies support the hypothesis that lowering serum CRP and LDL-C should be "dual" goals of statin therapy [139]. Prospective randomized trials are necessary to evaluate this hypothesis.

Other lipid-lowering agents — Among 18,144 patients in the IMPROVE IT-TIMI 22 trial who were stabilized after an ACS and randomized to simvastatin or ezetimibe/simvastatin, the addition of ezetimibe to a statin resulted in a 0.3 mg/L (16 percent) reduction in the median hs-CRP at one month and a 0.3 mg/L (14 percent) reduction over the study duration in comparison with simvastatin monotherapy [140]. This effect of ezetimibe on hs-CRP translated to significantly more patients meeting both of the "dual" goals of LDL-C <70 mg/dL and hs-CRP <2 mg/L in the ezetimibe/simvastatin group in comparison with simvastatin alone (50 versus 29 percent). Patients achieving these "dual" goals had a lower rate of major cardiovascular events than patients meeting neither target (cardiovascular death, major coronary event, or stroke; 39 versus 28 percent; adjusted hazard ratio [HR] 0.73; 95% CI 0.66-0.81).

Anti-inflammatory agents — Therapies that reduce inflammation should, in theory, reduce the adverse effects of atherosclerosis.

Monoclonal antibodies — In the CANTOS trial, which enrolled 10,061 patients with a recent ACS and hs-CRP level ≥2 mg/L, patients were randomly assigned to receive one of three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every three months), a monoclonal antibody targeting the interleukin-1 beta, or to placebo [141]. The primary efficacy end point was nonfatal MI, nonfatal stroke, or cardiovascular death. Compared with patients receiving placebo (4.50 events per 100 person-years), both the 150 mg (3.86 events per 100 person-years; HR 0.85; 95% CI 0.74-0.98) and 300 mg (3.90 events per 100 person-years; HR 0.86; 95% CI 0.75-0.99) doses of canakinumab resulted in a significant reduction of the primary end point. Canakinumab was associated with a significantly higher incidence of fatal infection than was placebo (0.31 versus 0.18 events per 100 person-years). Canakinumab had no effects on lipid levels, while it resulted in a dose-dependent reduction of CRP levels. In a prespecified secondary analysis, patients who achieved an on-treatment hs-CRP level <2 mg/L had significant reductions in total mortality (adjusted HR 0.69; 95% CI 0.58-0.81), cardiovascular mortality, and major adverse cardiovascular events when compared with patients receiving placebo; no significant reductions in these outcomes were seen in patients whose on-treatment hs-CRP level remained ≥2 mg/L [142].

This is the first study to show that an anti-inflammatory drug with no effect on lipid levels improves the outcome of patients with ACS and systemic evidence of inflammation (elevated hs-CRP), therefore proving the inflammatory hypothesis of ACS [141]. However, since the benefit of canakinumab on ischemic events was modest while it was associated with a higher risk of fatal infections, further studies are needed to confirm the safety and efficacy of this therapy, as well as to potentially identify other forms of anti-inflammatory treatments with a more favorable risk/benefit ratio. Canakinumab is not universally available for secondary prevention of ASCVD.

Aspirin — Although aspirin does not reduce serum CRP in apparently healthy men [143], serum CRP appears to influence the reduction in the relative risk of vascular disease induced by aspirin. In a report of healthy men from the Physicians' Health Study, the risk reduction with aspirin was much greater in those in the upper quartile of serum CRP compared with the lower quartile (56 versus 14 percent) [47]. The clinical use of aspirin in primary and secondary CVD prevention are discussed separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Other therapies — Treatment with a variety of other medications, including thiazolidinediones and beta blockers, has been associated with lower levels of CRP, as has a diet rich in fiber and vegetables [144-153]. Conversely, CRP levels appear to increase in women using menopausal hormone therapy [154-156]. The clinical significance of these observations remains uncertain.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Assessment of cardiovascular risk".)

SUMMARY AND RECOMMENDATIONS

●Pathogenic mechanisms for ASCVD – Inflammation is a known factor in the development of atherosclerosis and subsequent atherosclerotic cardiovascular disease (ASCVD) events. The most extensively studied biomarker of inflammation in ASCVD is C-reactive protein (CRP). Despite a lack of specificity for the cause of inflammation, data from numerous epidemiologic studies have shown a significant association between elevated serum or plasma concentrations of CRP and the prevalence of underlying atherosclerosis, the risk of recurrent cardiovascular events among patients with established disease, and the incidence of first cardiovascular events among individuals at risk for atherosclerosis. (See 'Introduction' above and 'Possible pathogenic role of CRP' above.)

●Definition of normal – While the ideal value that constitutes a high serum high-sensitivity CRP (hs-CRP; and increased cardiovascular risk) is not clearly defined, ranges articulated by the Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA) for the use of serum hs-CRP to estimate cardiovascular risk are employed when hs-CRP is measured for this purpose. There is no standardized CRP value that can be considered normal. However, individuals with values <1 mg/L have been considered to be at lowest risk, with low-, average-, and high-risk values defined as <1, 1 to 3, and >3 mg/L. (See 'Clinical context' above.)

●Observational studies – Several large population-based studies evaluating CRP in unselected asymptomatic populations have shown that, among apparently healthy individuals, the baseline level of CRP is associated with the long-term risk of a first myocardial infarction (MI), ischemic stroke, hypertension, peripheral vascular disease, sudden cardiac death, and all-cause mortality. While serum CRP does appear to act as an independent predictor of ASCVD in the general population, the predictive value added to that determined by screening for other coronary risk factors is small. (See 'Association of CRP with cardiovascular risk' above.)

●Role in screening for CVD risk – The use of hs-CRP to screen the general population for cardiovascular risk is controversial. While some experts recommend the routine measurement of hs-CRP at the time of cholesterol screening to be used as adjunctive data in the overall assessment of cardiovascular risk, we continue to prioritize the assessment of traditional risk factors and consider hs-CRP primarily for those with intermediate cardiovascular risk as determined using traditional risk factors and one or more of the available risk calculators. (See 'Our approach' above and "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

•Screening patients at low risk for ASCVD using hs-CRP has not been shown to change the current recommendations of lifestyle modifications in such individuals. Similarly, screening individuals at high risk for ASCVD with hs-CRP would not change current guideline-based management of established risk factors. Therefore, we do not recommend a strategy of routinely measuring hs-CRP in unselected populations to screen for ASCVD (Grade 2C).

•For patients at intermediate risk for CVD using traditional risk factors and contemporary risk calculators (ie, 10 to 20 percent risk at 10 years) for whom a more definite estimate of cardiovascular risk might change their individual decision about whether or not to initiate statin therapy, we suggest a screening measurement of hs-CRP (Grade 2C).

●Role in lipid-lowering therapy decision – The JUPITER trial suggests that the measurement of hs-CRP might help in the identification of asymptomatic patients at intermediate risk of cardiovascular events who may benefit from lipid-lowering treatment if CRP is >2 mg/L. This information may be particularly useful in patients at intermediate risk who exhibit risk factors not incorporated in current risk stratification tools like a family history of early ischemic heart disease, obesity, and/or sedentary life. (See 'Statins' above.)

●Role in anti-inflammatory treatment – The CANTOS trial suggests that patients with a history of MI and hs-CRP >2 mg/L may benefit from an anti-inflammatory treatment. However, the role of anti-inflammatory treatment for patients post ACS remains to be determined. (See 'Monoclonal antibodies' above.)