A 63-year-old woman with hypertension presents to your clinic for routine follow-up. She came across an online article regarding C-reactive protein and its purported link to heart disease, and she asks you whether she should be tested for it. She is an otherwise asymptomatic non-smoker without a family history of heart disease. Her only medication is hydrochlorothiazide. Her blood pressure measured in the office is 128/81 mmHg, her low-density lipoprotein is 110 mg/dL, and her high-density lipoprotein is 54 mg/dL. What do you tell her?
What is CRP?
C-reactive protein (CRP) is an acute-phase reactant produced by the liver in response to the inflammatory cytokines interleukin-6 and interferon. CRP primarily mediates the inflammatory response by binding to complement and damaged cell membranes, but it has also been noted to bind to low-density lipoprotein (LDL) . Common stimuli of high CRP levels (conventionally defined as >3 mg/L) include infection, cancer, and surgery. CRP also increases to intermediate levels (1-3 mg/L) with age, obesity, smoking, gum disease, and related co-morbidities such as chronic lung disease, diabetes, and hypertension . Interestingly, the variability of multiple CRP measurements in the same person over time exhibits stability comparable to blood pressure and cholesterol . While early measurements of CRP only detected levels greater than 3 mg/L, later studies capitalized on the development of improved high-sensitivity CRP (hs-CRP) assays, which detect levels as low as 0.1 mg/L.
With respect to healthy adults, studies show a positive correlation between elevated CRP levels and development of coronary heart disease, independent of other risk factors. A meta-analysis of 54 observation studies characterized this relationship as a log-linear association when adjusted for age and sex . A 2009 meta-analysis of 11 good-quality studies calculated a relative risk of 1.58 (confidence interval 1.37-1.83) for the development of coronary artery disease in the high versus low serum CRP groups. The studies all adjusted for Framingham risk factors beforehand. The corresponding risk ratio for the intermediate versus low serum CRP groups was 1.22 (confidence interval 1.11-1.33) . This relationship persists in individuals with known cardiovascular disease, with higher CRP values portending a worse prognosis. For instance, stable coronary artery disease subjects with a fairly even distribution of low, intermediate, and high serum CRP categories showed a statistically significant increased risk of cardiovascular death, myocardial infarction, or stroke in the intermediate CRP group compared with low CRP group (adjusted hazard ratio of 1.39). The adjusted hazard ratio rose to 1.52 for high CRP group compared to the low CRP group .
Does CRP play a pathologic role in atherosclerosis?
Multiple studies demonstrate an association between elevated CRP and increased risk of heart disease, regardless of prior cardiovascular disease diagnosis. However, it is unclear if a causal mechanism governs this association. Do high CRP levels drive atherosclerosis, or are they simply a marker of disease? Atherosclerotic plaques stain positive for CRP, but the evidence for causality is less clear . Proposed avenues for CRP-induced plaque build-up include monocyte adhesion and recruitment into the vessel walls, macrophage activation, and smooth muscle cell proliferation. Moreover, binding to LDL facilitates LDL oxidation and uptake by macrophages. CRP also interferes with endothelial nitric oxide synthase function and prostacyclin synthesis, leading to decreased vasodilation .
In addition, CRP’s classification as an acute-phase reactant and its subsequent association with inflammatory conditions offer numerous confounding variables. On one hand, lower CRP levels after statin therapy are associated with a lower risk of recurrent myocardial infarction or coronary fatalities, regardless of post-statin LDL levels . Post hoc analyses of the PROVE-IT trial demonstrated that lower CRP was significantly and independently associated with slower progression of atherosclerosis as measured by intravascular ultrasound over 18 months [9,10]. This suggests a direct link between CRP and cardiovascular risk independent of LDL levels.
On the other hand, scenarios that attempt to directly influence or change CRP levels do not necessarily maintain this link. For example, murine models of atherosclerosis do not reliably show increased plaque build-up in transgenic mice designed to produce human CRP . One mendelian randomization study from 2008 calculated whether naturally-occurring genetic polymorphisms in the CRP gene and subsequent variations in serum CRP levels could predict cardiovascular outcomes. Genetic variation was responsible for up to 64% change in CRP level, but this did not translate into a statistically significant increased odds ratio for ischemic heart disease. In contrast, different apolipoprotein E genotypes accounted for up to a 14% change in cholesterol level, with a statistically significant increased odds ratio of 1.29 for development of ischemic heart disease . A later mendelian randomization study also did not find a statistically significant relationship between genetically-raised CRP levels and the development of heart disease .
How to Use CRP in Clinical Practice
To date, the main randomized clinical trial that examines CRP and cardiovascular risk is the JUPITER trial published in 2008. This trial evaluated rosuvastatin 20mg daily for primary prevention in healthy adults who demonstrated both LDL <130 and hs-CRP >2. The trial was stopped early at the first interim analysis because the statin’s benefit was clear. After a median of 1.9 years of follow-up, a statistically significant reduction in the primary outcome (a composite of heart attack, stroke, unstable angina, revascularization, or cardiovascular death) was found for the statin group as compared to placebo (hazard ratio 0.56, 95% confidence interval 0.46 to 0.59) . This suggested a role for CRP in selecting additional patients who would benefit from statins. Although the trial only included patients with higher levels of hs-CRP, a post hoc analysis demonstrated a consistent association between higher baseline hs-CRP and increased frequency of the primary outcome . Of note, the trial was criticized on the grounds of conflict of interest, as the principal investigator co-owns the patent for the hs-CRP blood test used in the study .
In 2003, the Centers for Disease Control and Prevention and the American Heart Association recommended against universal screening for cardiovascular risk with CRP. The document identified intermediate-risk patients as the population for which it is reasonable to measure hs-CRP twice, 2 weeks apart, for further risk stratification . In healthy asymptomatic adults with an intermediate Framingham risk of 5-20%, the addition of CRP appropriately reclassified only 4.3% of subjects into the high-risk category, and only 3.6% into the low-risk category . According to one model developed prior to the updated statin therapy guidelines, testing the CRP of 440 intermediate-risk patients without a coronary heart disease equivalent is needed in order to reclassify 23 individuals as high-risk. If those 23 subjects initiated statin therapy, then 1 cardiovascular event (myocardial infarction, stroke, or fatal coronary heart disease) would be averted. In effect, the number needed to “test” of 440 would avert 1 cardiovascular event over 10 years, assuming appropriate statin interventions based on the 2002 Adult Treatment Panel III guidelines . However, studies that have compared the accuracy of CRP versus coronary artery calcium score and carotid intima-media thickness in reclassifying intermediate-risk patients found that coronary artery calcium score and carotid intima-media thickness both outperformed CRP .
More recent guidelines still fail to offer compelling indications for CRP utilization. In fact, the 2009 US Preventive Services Task Force stated that there was insufficient evidence for the use of hs-CRP for cardiovascular risk assessment . Two simultaneously released guidelines in November 2013 from the American College of Cardiology/American Heart Association (ACC/AHA), on the topics of cholesterol and on cardiovascular risk assessment, discuss a possible role for hs-CRP in patients who do not fall into the outlined four major statin benefit groups or who have unclear risk even after quantitative risk assessment. The recommendation to consider hs-CRP use under these select circumstances is based on expert opinion only, and does not distinguish between CRP versus other novel risk factors such as coronary artery calcium score and ankle-brachial index [20,21]. The new guidelines also suggest hs-CRP >2 as the threshold for upgrading the level of cardiovascular risk for a patient.
In summary, existing evidence tentatively suggests that CRP is an independent risk factor for heart disease; however, in the absence of data examining universal CRP screening, hard clinical outcomes, mortality, or cost effectiveness, the current recommendations are to use CRP sparingly under select circumstances. In the clinic, CRP may be used as a tool for further risk stratification of intermediate-risk patients in order to select candidates who may benefit the most from additional interventions and therapies.
With regards to the clinical vignette, this patient does not fall into one of the 4 major statin benefit groups, as outlined in the newly released 2013 ACC/AHA guidelines. Her calculated 10-year risk of atherosclerotic cardiovascular disease is 6%, which does not reach the threshold of 7.5% for starting a statin. According to the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk document, expert opinion states that hs-CRP may have a role in determining whether to begin statin therapy. If her measured hs-CRP were greater than 2, one may consider upgrading her risk level and adding a statin for primary prevention, with the knowledge that this recommendation is based on very limited data.
Commentary By Robert Donnino, MD Assistant Professor of Medicine (Cardiology)
The use of hs-CRP for cardiovascular risk stratification remains highly controversial. Analysis of existing data suggests that CRP is, at best, a weak independent risk factor for clinical cardiovascular events. Without the inclusion of patients with CRP < 2 in the JUPITER trial (Ridker et al., reference 8 from above), it cannot be concluded that the CRP level of >2 conferred any increased risk, nor does it identify patients who would have received additional benefit with statin therapy. This has led many to question whether patients with CRP < 2 would have received similar benefits from statin therapy if they had been included in the trial.
As mentioned in this overview on CRP, data published from the MESA cohort showed CRP was not a very effective tool for reclassifying intermediate risk patients into higher or lower risk groups, reclassifying a total of only 8% of patients (Yeboah, et al; reference 17 from above). For comparison, coronary calcium score in that same cohort reclassified 66% of patients into higher or lower risk groups. Other studies have even lower reclassification ability for CRP. Thus, although supported by current guidelines and followed by some practitioners, I believe the data do not support the use of CRP as a risk stratification tool and that much more powerful stratification tools are available (i.e. coronary calcium score). For more in-depth analysis of CPR for cardiovascular risk, I would recommend the excellent review by Yousuf and colleages (reference 7 from above). Until we have more clarifying data, the role of CRP in clinical practice will remain controversial.
Dr. Cindy Fei is an internist at NYU Langone Medical Center
Peer review by Robert Donnino, MD, Assistant Professor of Medicine (Cardiology), NYU Langone Medical Center
Image courtesy of Wikimedia Commons
- Scirica BM, Morrow DA. Is C-reactive protein an innocent bystander or proatherogenic culprit? The verdict is still out. Circulation 2006;113(17): 2128-2134.
- Windgassen EB, Funtowicz L, Lunsford TN, Harris LA, Mulvagh SL. C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians Postgrad Med 2011;123(1): 114-119. http://www.ncbi.nlm.nih.gov/pubmed/21293091
- Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. NEJM 2004;350(14): 1387-1397.
- Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis Lancet 2010;375(9709): 132-140. http://www.ncbi.nlm.nih.gov/pubmed/20031199
- Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151(7): 483-495. http://www.ncbi.nlm.nih.gov/pubmed/19805771
- Sabatine MS, Morrow DA, Jablonski KA, et al. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation 2007;115(12): 1528-1536. http://www.ncbi.nlm.nih.gov/pubmed/17372173
- Yousuf O, Mohanty BD, Martin SS, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol 2013;62(5): 397-408. http://www.ncbi.nlm.nih.gov/pubmed/23727085
- Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. NEJM 2005;352(1): 20-28. http://www.nejm.org/doi/full/10.1056/NEJMoa042378
- Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. NEJM 2004;350(15): 1495-1504. http://www.nejm.org/doi/full/10.1056/NEJMoa040583
- Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. NEJM 2005;352(1): 29-38. http://www.nejm.org/doi/full/10.1056/NEJMoa042000
- Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. NEJM 2008;359(18): 1897-1908. http://www.ncbi.nlm.nih.gov/pubmed/18971492
- C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC), Wensley F, Gao P, et al. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 2011;342:d548. http://www.ncbi.nlm.nih.gov/pubmed/21325005
- Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein NEJM 2008;359(21): 2195-2207. http://www.nejm.org/doi/full/10.1056/NEJMoa0807646
- Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Am J Cardiol 2010;106(2): 204-209. http://www.ncbi.nlm.nih.gov/pubmed/20599004
- de Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med 2010;170(12): 1032-1036. http://archinte.jamanetwork.com/article.aspx?articleid=416101
- Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107(3): 499-511.
- Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals JAMA 2012;308(8): 788-795. http://jama.jamanetwork.com/article.aspx?articleid=1352110
- Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction NEJM 2012;367(14): 1310-1320. http://www.ncbi.nlm.nih.gov/pubmed/23034020
- US Preventive Services Task Force. Using Nontraditional Risk Factors In Coronary Heart Disease Risk Assessment. Oct 2009. Accessed Nov 2013. http://www.uspreventiveservicestaskforce.org/uspstf/uspscoronaryhd.htm
- Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation http://www.ncbi.nlm.nih.gov/pubmed/24222016
- Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation http://www.ncbi.nlm.nih.gov/pubmed/24222018