Neutrophil lymphocyte ratio significantly improves the Framingham risk score in prediction of coronary heart disease mortality: Insights from the National Health and Nutrition Examination Survey-III

https://doi.org/10.1016/j.ijcard.2013.12.019Get rights and content

Abstract

Background

Neutrophil lymphocyte ratio (NLR) has been shown to predict cardiovascular events in several studies. We sought to study if NLR predicts coronary heart disease (CHD) in a healthy US cohort and if it reclassifies the traditional Framingham risk score (FRS) model.

Methods

We performed post hoc analysis of National Health and Nutrition Examination Survey-III (1998–94) including subjects aged 30–79 years free from CHD or CHD equivalent at baseline. Primary endpoint was death from ischemic heart disease. NLR was divided into four categories: < 1.5, ≥ 1.5 to < 3.0, 3.0–4.5 and > 4.5. Statistical analyses involved multivariate Cox proportional hazards models as well as discrimination, calibration and reclassification.

Results

We included 7363 subjects with a mean follow up of 14.1 years. There were 231 (3.1%) CHD deaths, more in those with NLR > 4.5 (11%) compared to NLR < 1.5 (2.4%), p < 0.001. Adjusted hazard ratio of NLR > 4.5 was 2.68 (95% CI 1.07–6.72, p = 0.035). There was no significant improvement in C-index (0.8709 to 0.8713) or area under curve (0.8520 to 0.8531) with addition of NLR to FRS model. Model with NLR was well calibrated with Hosmer–Lemeshow chi-square of 8.57 (p = 0.38). Overall net reclassification index (NRI) was 6.6% (p = 0.003) with intermediate NRI of 10.1% (p < 0.001) and net upward reclassification of 5.6%. Absolute integrated discrimination index (IDI) was 0.003 (p = 0.039) with relative IDI of 4.3%.

Conclusions

NLR can independently predict CHD mortality in an asymptomatic general population cohort. It reclassifies intermediate risk category of FRS, with significant upward reclassification. NLR should be considered as an inflammatory biomarker of CHD.

Introduction

Cardiovascular disease is the leading cause of death in United States. Statistics from 2009 show nearly 600,000 annual deaths due to cardiovascular disease, out of which 385,000 deaths were due to coronary heart disease (CHD) [1]. The annual cost attributed to CHD in US is around $109 billion [1]. CHD has a long latent period during which the subjects remain asymptomatic. In order to reduce the burden of CHD, an important step is to institute appropriate primary prevention measures in asymptomatic, apparently healthy population at risk. Traditional risk assessment strategies for CHD like the Framingham risk score (FRS) rely on markers like age, sex, hypertension, diabetes, hyperlipidemia and smoking. Unfortunately, conventional risk prediction models like FRS often fail to identify a considerable proportion of individuals at risk of developing CHD. Almost half of individuals who develop CHD have only 1 or none of these traditional risk factors [2], [3]. Hence there is a need to improve the currently existing risk assessment models for more accurate prediction of CHD risk, so that targeted preventive measures can be instituted.

The 2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines [4] recommend that initially global risk scores like FRS should be applied to all asymptomatic individuals for risk assessment. Persons at low risk do not need any further testing. Persons at high risk should be subjected to intensive preventive measures. Persons at intermediate risk may be considered to undergo further stratification by using either serum or radiologic markers, as long as these tests are cost effective [4]. The serum markers proposed by ACCF/AHA [4] include C-reactive protein (CRP), brain natriuretic peptide (BNP), hemoglobin A1c and lipoprotein associated phospholipase A2. The role of neutrophil lymphocyte ratio (NLR) as a biomarker for CHD in asymptomatic individuals is not clear. NLR is a simple ratio of the absolute neutrophil and lymphocyte counts obtained on the differential section of leukocyte count of a complete blood count (CBC) and is a marker of inflammation. NLR has been shown to be associated with worse outcomes in patients with acute coronary syndromes and established CHD [5], [6], [7], [8], [9], [10], [11], [12]. However, there is a lack of data regarding its role in healthy individuals free from CHD at baseline. We sought to study the value of NLR to predict CHD related mortality in the National Health and Nutrition Examination Survey-III (NHANES-III) cohort which is representative of a healthy US general population cohort.

Section snippets

Study sample and design

NHANES-III, conducted by the National Center for Health Statistics, includes data from oral surveys and general health examinations. It was designed to assess the demographic, socioeconomic, dietary and overall health status of a representative sample from all 50 States. Of the individuals selected to participate, 30,818 subjects (with 19,215 adults ≥ 18 years age) completed the health examination [13].

Our study inclusion criteria were subjects aged 30–79 years who did not have a history of

Results

We included 7363 subjects, who took part in NHANES-III from 1988 to 1994. This was representative of 89,80,0451 (almost 9 million) US general population. The mean follow up period was 14.1 ± 3.2 years. The number of CHD related deaths over this period was 231 (3.14%), signifying overall low risk in the population.

Discussion

Our study showed that neutrophil lymphocyte ratio (NLR) is an independent predictor of cardiovascular mortality in a nationally representative general population cohort. Moreover, NLR accurately reclassified those in the intermediate risk category of the Framingham Risk Score (FRS) as having lower or higher probability of cardiovascular mortality. NLR has been shown to be predictive of all cause and cardiovascular mortality in patients with acute coronary syndromes (ACS) [5], [6], [7], [8], [9]

Conclusions

NLR is a potential independent predictor of CHD mortality in a cross sectional US population. Adding NLR to the Framingham risk score model marginally improves model discrimination and significantly improves model calibration. There is significantly better reclassification of individuals in intermediate risk category of FRS with NRI of 10.1% and upward reclassification of 5.6%. NLR fulfills the criteria to be considered as a biomarker for predicting future CHD risk in asymptomatic, apparently

References (91)

  • V. Menon et al.

    Leukocytosis and adverse hospital outcomes after acute myocardial infarction

    Am J Cardiol

    (2003)
  • S.R. Ommen et al.

    Usefulness of the lymphocyte concentration as a prognostic marker in coronary artery disease

    Am J Cardiol

    (1997)
  • E.G. Zouridakis et al.

    Usefulness of the blood lymphocyte count in predicting recurrent instability and death in patients with unstable angina pectoris

    Am J Cardiol

    (2000)
  • M. Akpek et al.

    Relation of neutrophil/lymphocyte ratio to coronary flow to in-hospital major adverse cardiac events in patients with ST-elevated myocardial infarction undergoing primary coronary intervention

    Am J Cardiol

    (2012)
  • J.T. Neumann et al.

    Association of MR-proadrenomedullin with cardiovascular risk factors and subclinical cardiovascular disease

    Atherosclerosis

    (2013)
  • J.J. Cao et al.

    Cardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68–102: the Cardiovascular Health Study

    Atherosclerosis

    (2008)
  • N.M. Shara et al.

    Comparison of estimated glomerular filtration rates and albuminuria in predicting risk of coronary heart disease in a population with high prevalence of diabetes mellitus and renal disease

    Am J Cardiol

    (2011)
  • A.O. Badheka et al.

    ST-T wave abnormality in lead aVR and reclassification of cardiovascular risk (from the National Health and Nutrition Examination Survey-III)

    Am J Cardiol

    (2013)
  • A.O. Badheka et al.

    QRS duration on electrocardiography and cardiovascular mortality (from the National Health and Nutrition Examination Survey-III)

    Am J Cardiol

    (2013)
  • V. Nambi et al.

    Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study

    J Am Coll Cardiol

    (2010)
  • S.E. Elias-Smale et al.

    Coronary calcium score improves classification of coronary heart disease risk in the elderly: the Rotterdam study

    J Am Coll Cardiol

    (2010)
  • T.P. Murphy et al.

    Ankle-brachial index and cardiovascular risk prediction: an analysis of 11,594 individuals with 10-year follow-up

    Atherosclerosis

    (2012)
  • C. Vlachopoulos et al.

    Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis

    J Am Coll Cardiol

    (2010)
  • P. Greenland et al.

    ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography

    J Am Coll Cardiol

    (2007)
  • H.C. Kim et al.

    Multimarker prediction of coronary heart disease risk: the Women's Health Initiative

    J Am Coll Cardiol

    (2010)
  • B. o Hartaigh et al.

    Which leukocyte subsets predict cardiovascular mortality? From the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study

    Atherosclerosis

    (2012)
  • G.J. Guthrie et al.

    The systemic inflammation-based neutrophil–lymphocyte ratio: Experience in patients with cancer

    Crit Rev Oncol Hematol

    (2013)
  • K.D. Kochanek et al.

    Deaths: Final Data for 2009

    Natl Vital Stat Rep

    (2011)
  • U.N. Khot et al.

    Prevalence of conventional risk factors in patients with coronary heart disease

    JAMA

    (2003)
  • P. Greenland et al.

    Major risk factors as antecedents of fatal and nonfatal coronary heart disease events

    JAMA

    (2003)
  • P. Greenland et al.

    ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

    Circulation

    (2010)
  • B. Azab et al.

    Neutrophil-lymphocyte ratio as a predictor of major adverse cardiac events among diabetic population: a 4-year follow-up study

    Angiology

    (2013)
  • Plan and operation of the Third National Health and Nutrition Examination Survey, 1988–94. Series 1: programs and collection procedures

    Vital Health Stat

    (1994)
  • E.W. Gunter et al.

    Laboratory procedures used for the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994

  • Executive summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)

    JAMA

    (2001)
  • J.L. Schafer

    Analyzing the NHANES III multiply imputed data set: methods and examples

    Prepared for the National Center for Health, Statistics

    (2001)
  • N.R. Cook

    Use and misuse of the receiver operating characteristic curve in risk prediction

    Circulation

    (2007)
  • J.A. Hanley et al.

    The meaning and use of the area under a receiver operating characteristic (ROC) curve

    Radiology

    (1982)
  • D.W. Hosmer et al.

    Goodness of fit tests for the multiple logistic regression model

    Commun Stat A Theory Methods

    (1980)
  • M.J. Pencina et al.

    Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond

    Stat Med

    (2008)
  • G. Huang et al.

    Significance of white blood cell count and its subtypes in patients with acute coronary syndrome

    Eur J Clin Invest

    (2009)
  • M. Kruk et al.

    Association of non-specific inflammatory activation with early mortality in patients with ST-elevation acute coronary syndrome treated with primary angioplasty

    Circ J

    (2008)
  • P. Libby

    Inflammation in atherosclerosis

    Arterioscler Thromb Vasc Biol

    (2012)
  • R. Ross

    Atherosclerosis—an inflammatory disease

    N Engl J Med

    (1999)
  • L. Jonasson et al.

    Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque

    Arteriosclerosis

    (1986)
  • Cited by (133)

    View all citing articles on Scopus
    View full text