Accepted Manuscript

Title: Usefulness of Platelet-to-Lymphocyte Ratio to Predict Long-Term All-

Cause Mortality in Patients at High Risk of Coronary Artery Disease
Undergoing Coronary Angiography

Author: Yun Suk G. Lee, Arul Baradi, Matthew Peverelle, Rohullah Sultani,
Heath Adams, John Garlick, Andrew M. Wilson

PII: S0002-9149(18)30160-7
DOI: https://doi.org/10.1016/j.amjcard.2018.01.018
Reference: AJC 23096

To appear in: The American Journal of Cardiology

Received date: 18-10-2017

Accepted date: 8-1-2018

Please cite this article as: Yun Suk G. Lee, Arul Baradi, Matthew Peverelle, Rohullah Sultani,
Heath Adams, John Garlick, Andrew M. Wilson, Usefulness of Platelet-to-Lymphocyte Ratio to
Predict Long-Term All-Cause Mortality in Patients at High Risk of Coronary Artery Disease
Undergoing Coronary Angiography, The American Journal of Cardiology (2018),
https://doi.org/10.1016/j.amjcard.2018.01.018.

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 Usefulness of Platelet-to-Lymphocyte Ratio to Predict Long-Term All-Cause Mortality in

Patients at High Risk of Coronary Artery Disease Undergoing Coronary Angiography

Yun Suk G. Lee, MDa, Arul Baradi, MBChBa,b, Matthew Peverelle, MDa, Rohullah Sultani, MDa,

Heath Adams, MBBSb, John Garlick, PhDa, Andrew M. Wilson, MBBS, PhDa,b,c,*

a
University of Melbourne, Department of Medicine, St Vincent’s Hospital, Melbourne, Australia
b
Department of Cardiology, St Vincent’s Hospital, Melbourne, Australia
c
Australian Catholic University, Melbourne, Australia

*Corresponding author: Department of Medicine, University of Melbourne, St Vincent’s

Hospital, Melbourne, 4th Floor Clinical Sciences Building, 29 Regent Street, Fitzroy, Victoria,

Australia 3065. EMAIL: Andrew.WILSON@svha.org.au TEL: +61 3 9231 2574

FAX: +61 3 9231 4422 (A. M. Wilson).

Grant support: Andrew M. Wilson is supported by grants from the National Heart Foundation of

Australia, Diabetes Australia Research Trust and the Australian Catholic University (Melbourne,

Victoria, Australia). Arul Baradi is supported by an Australian Government Research Training

Program Scholarship and NHMRC Centre of Research Excellence in Cardiovascular Outcomes

Improvement (CRE-COI) PhD Scholarship (Melbourne, Victoria, Australia).

Running title: High PLR and long-term mortality

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Abstract

Platelet-to-lymphocyte ratio (PLR) has recently been studied as a biomarker in patients with

established coronary artery disease (CAD). The association between PLR and long-term all-

cause mortality is unclear in patients at high risk of CAD undergoing coronary angiography for

various indications. Follow-up was completed for 514 patients who underwent coronary

angiography in a prospective study cohort. The primary endpoint was all-cause mortality.

Patients were classified into tertiles based on pre-angiography PLR and also dichotomized based

on the optimal cut-off at PLR of 137, determined from the receiver-operating characteristic curve

analysis. The mean follow-up period was 5 ± 1.3 years, with 50 all-cause deaths. On the Kaplan-

Meier analysis, patients in Tertile 3 (PLR >145) had worse prognosis than patients in Tertiles 1

(PLR ≤106) and 2 (PLR between 106.1 and 145) (p = 0.0075), and patients with PLR ≥137 had a

significantly higher rate of all-cause mortality than those with PLR <137 (p = 0.0006). On

multivariate Cox regression adjusting for known cardiovascular risk factors, PLR was a strong,

independent predictor of long-term all-cause mortality on the tertile analysis (Tertile 3 vs. 1:

hazard ratio [HR] 2.52, 95% confidence interval [CI] 1.18 to 5.39, p = 0.017) and based on the

cut-off at PLR of 137 (PLR ≥137 vs. <137: HR 2.25, 95% CI 1.21 to 4.20, p = 0.011). In

conclusion, elevated PLR is associated with long-term all-cause mortality in patients at high risk

of CAD undergoing coronary angiography and PLR may be a useful prognostic biomarker in this

population.

Keywords: platelet-to-lymphocyte ratio, coronary artery disease, prognosis, coronary

angiography

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Inflammation and thrombosis are central pathways implicated in the progression of

atherosclerosis and coronary artery disease (CAD)1. Platelet-to-lymphocyte ratio (PLR) has

received growing interest in cardiovascular medicine as a novel, inexpensive and readily

available biomarker for prognosis for its improved stability and statistical power that combines

information from both pathways of hemostasis and inflammation2-6. Higher PLR was shown to

predict long-term major adverse cardiovascular events (MACE)7,8, as well as all-cause mortality

in patients with stable CAD9, with non-ST-elevation myocardial infarction (non-STEMI)2 and

with diabetes and STEMI10. PLR was also associated with no-reflow phenomenon and higher

Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery

(SYNTAX) score11,12. Research is however scarce regarding the association of PLR and all-

cause mortality in patients at high risk of CAD undergoing coronary angiography, especially at

an extended period of follow-up (≥5 years). The aim of this present study is to investigate the

prognostic value of PLR in predicting long-term all-cause mortality in patients undergoing

coronary angiography for various indications who were at high risk of CAD.

Methods

The study population was identified from the Biomarkers of Atherosclerosis, Vascular

and Endothelial Dysfunction in Heart Disease (BRAVEHEART) Study. The BRAVEHEART

study is a prospective cohort study that consecutively recruited patients admitted to St Vincent’s

Hospital, Melbourne for coronary angiography/percutaneous coronary intervention (PCI)

between October 2009 and May 2013, excluding patients with acute or chronic infections,

systemic inflammatory conditions, recent or untreated malignancies and serum creatinine levels

>160µmol/L. We included 514 of the 850 patients in the BRAVEHEART cohort. We excluded

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patients with incomplete data and those who either refused to take part in the study or were

unable to be contacted at the end of the follow-up period.

Baseline demographic and medical data were obtained from detailed medical records

taken during the hospital admission. Hypertension was defined as a previous diagnosis or current

use of anti-hypertensive medications. Diabetes was defined as a previous diagnosis or current use

of anti-diabetic medications. Hypercholesterolemia was defined as a previous diagnosis or

current use of cholesterol medications. Smoker was defined as current, regular use of cigarettes.

Clinical measurements were also taken at admission, including height, weight, systolic and

diastolic blood pressure. Laboratory parameters were measured at admission using blood

samples obtained from the venepuncture performed prior to the angiography. Full blood

examination including white blood cell with differential count and platelet count was analyzed in

ethylenediaminetetraacetate tube by automatic cell analyzer. Creatinine was automatically

analyzed from a serum separator tube, sampled during the same venepuncture. PLR was

computed as absolute platelet count divided by absolute lymphocyte count, both obtained from

the same blood sample. Coronary angiography was reviewed by an experienced interventional

cardiologist. The presence of CAD was determined angiographically, defined by the presence of

50% or more stenosis in at least 1 of the main coronary arteries or previous PCI for a stenotic

coronary artery.

The primary endpoint was all-cause mortality. Survival status was determined from the

hospital records or during the follow-up conducted between March and June 2016, using a

standard, structured telephone questionnaire. Multiple attempts were made to contact the patients,

their family members and their primary care physician. This study was approved by the Human

Research Ethics Committee at St Vincent’s Hospital, Melbourne. Study participants were invited

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to participate before the follow-up questionnaire and informed consent was obtained.

Continuous variables were expressed as mean ± standard deviation and categorical

variables were expressed as number (%). The analysis of the study population was stratified

according to the PLR tertile groups based on their pre-angiography PLR. A receiver-operating

characteristic (ROC) curve analysis was also performed to ascertain the optimal cut-off value of

PLR to predict all-cause mortality. The best cut-off value for PLR was selected by the use of the

Youden index. On a separate analysis, the study population was also dichotomized based on this

PLR cut-off value. For comparison of baseline data, continuous variables were compared using

analysis of variance (between PLR tertile groups) or Student’s t test (between two dichotomized

groups) for normally distributed variables and Kruskal-Wallis test (between PLR tertile groups)

or Mann-Whitney U test (between two dichotomized groups) for non-normally distributed

variables. Categorical variables were compared using the chi-square test. Kaplan-Meier mortality

curves were constructed for the tertile groups and compared by log rank test. Similarly, separate

Kaplan-Meier mortality curves were drawn to compare the mortality rate when the study

participants were dichotomized based on the optimal cut-off value of PLR from the ROC curve

analysis. The usefulness of PLR to independently predict all-cause mortality was analyzed by the

Cox regression models. Multivariate Cox regression models were adjusted for established

cardiovascular risk factors (age, male gender, body mass index (BMI), hypertension, diabetes,

hypercholesterolemia and smoking) and CAD as evidenced on coronary angiography. A

threshold of p-value <0.05 was set for statistical significance. All statistical analyses were

performed using the STATA 14 software program (StataCorp, Texas, United States of America).

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Results

A total of 514 patients were included in the study, of which 354 were male (69%) and

160 were female (31%), with the mean ages of 63 ± 11 years and 65 ± 11 years, respectively.

The mean follow-up period was 5 ± 1.3 years and there were 50 all-cause deaths. Table 1

illustrates the baseline clinical and biochemical characteristics of each of the 3 groups based on

their pre-angiography PLR values (Tertile 1: PLR ≤106, Tertile 2: PLR between 106.1 and 145,

Tertile 3: PLR >145). Patients in Tertile 3 were more likely to be older and of lower BMI,

compared with patients in Tertile 1 who were more likely to be diabetic and had higher

hemoglobin A1c (HbA1c). By the nature of the tertile-based analysis, patients in Tertile 3 were

selected to have higher platelet count and PLR and lower total white cell count and lymphocyte

count. The ROC curve with analysis is shown in Figure 1 and the optimal cut-off value for PLR

to predict all-cause mortality was ascertained to be 137, which approximates the mean PLR of

the entire study population of 134. The area under the curve was 0.61 (95% confidence interval

[CI] 0.53 to 0.70, p = 0.01) with sensitivity of 62%, specificity of 63%, positive predictive value

of 15%, negative predictive value of 94% and diagnostic accuracy of 63%. When the study

population was dichotomized based on a PLR threshold of 137 (i.e. PLR ≥137 and PLR <137),

patients with PLR ≥137 were more likely to be older, of lower BMI and have lower HbA1c and

diastolic blood pressure. By design, they also had higher platelet count and PLR and lower

lymphocyte and total white cell counts than those with PLR <137.

Kaplan-Meier analysis (Figure 2) demonstrated worse long-term prognosis in Tertile 3

compared with Tertiles 1 and 2 (log rank, p = 0.0075). Individual comparisons of mortality rate

curves were also significantly different, between Tertiles 3 and 1 (p = 0.016) and between

Tertiles 3 and 2 (p = 0.009). Similar analysis was performed when the study population was

6
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dichotomized based on the optimal cut-off PLR value of 137 (Figure 3). Patients with PLR ≥137

had a significantly higher incidence of the primary endpoint compared with patients with PLR

<137 (log rank, p = 0.0006).

Multivariate Cox regression models (Table 2) were constructed with PLR as a continuous

variable (Model A), PLR tertile groups as a categorical variable (Model B) and PLR ≥137 or

<137 as a binary variable (Model C). All 3 models were adjusted for established cardiovascular

risk factors and CAD on coronary angiography. In Model A, PLR per 10-unit increase, age per

additional year and diabetes were independent predictors of all-cause mortality. In Model B,

Tertile 3, compared with Tertile 1, independently predicted the primary endpoint. Similarly, PLR

≥137 was independently predictive of all-cause mortality in Model C. Age per additional year

and diabetes remained as significant independent predictors in Model B and C.

Further multivariate Cox analysis was conducted that focused on a subset of the study

population who did not have acute myocardial infarction (AMI) at the time of coronary

angiography (Table 3). Similar to the analysis for the whole study population, PLR and long-

term all-cause mortality had a robust, independent association in the non-AMI subset of patients,

whether PLR was run as a continuous, categorical or binary variable.

Discussion

In our study, we demonstrated that admission PLR was associated with long-term all-

cause mortality in patients at high risk of CAD who underwent coronary angiography for various

indications. Patients in the highest PLR tertile (Tertile 3) had a significantly higher rate of the

primary endpoint compared with the lower 2 tertiles (Tertiles 1 and 2) and similar trend is seen

in the analysis based on the optimal cut-off at PLR of 137. In addition, we showed that PLR is a

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significant, independent predictor of long-term all-cause mortality in this population and also in a

subset of patients without AMI, after adjusting for known cardiovascular risk factors.

Our study patients were well-characterized, who were at high risk of CAD and all

underwent angiography thus defining coronary anatomy and prolonged follow-up. This is a key

difference compared to the population based studies. Moreover, previous studies that examined

PLR as a prognostic marker mostly had mean/median follow up periods of <5 years. Our study

therefore shows that PLR continues to predict outcome in the longer-term follow up of at least 5

years in this high-risk population.

A growing body of evidence demonstrates the prognostic utility of various parameters in

the complete blood count for outcome in cardiovascular disease. Previous studies examined the

association between poorer prognosis and higher platelet count in patients undergoing coronary

angiography3,13 and lower lymphocyte count in CAD14, unstable angina5 and advanced heart

failure patients4. Neutrophil-to-lymphocyte ratio (NLR) has also been studied and was

demonstrated to be a useful marker to predict angiographic no-reflow15, bare metal stent

restenosis16, MACE17 and all-cause mortality18-20.

PLR, which first gained attention in cancer patients as a marker for prognosis21,22, has

received growing interest of late with respect to its usefulness as a prognostic marker in

cardiovascular medicine. The proposed mechanism of platelet involvement is platelet activation

as a pivotal step of the inflammatory response in CAD and cardiovascular events23,24. During

inflammation, a variety of inflammatory mediators (e.g. interleukin (IL) 1, IL-3 and IL-6) are

released that stimulate megakaryocytes to proliferate and increase platelet levels in circulation12.

This relative thrombocytosis may reflect increased activation of thrombocytes and a

prothrombotic state8. Activated platelets promote a pro-inflammatory environment by secreting

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cytokines and coagulation factors, and they play a key role in the initiation and progression of

atherosclerosis25, atherosclerotic plaque instability and thrombus formation in the setting of

endothelial injury and plaque rupture12,23,26. On the other hand, lymphocytes are responsible for

providing a regulatory and quiescent pathway of inflammation5,12. Lymphopenia is commonly

observed in patients with myocardial ischemia, in the setting of increased physiologic stress and

increased cortisol and catecholamine levels27, and in high levels of inflammation that leads to

increased lymphocyte apoptosis28.

PLR has been considered as a superior prognostic marker to absolute platelet or

lymphocyte counts for several reasons. First, PLR is relatively more stable compared with

individual platelet or lymphocyte counts, which are more likely to be altered by different

physiologic and pathologic conditions2. Second, the ratio results in an increased statistical power

as systematic errors are cancelled out in ratios and noise in the dataset can be reduced6. Third,

PLR combines information from both pathways of hemostasis and inflammation and may be a

superior marker to predict impaired reperfusion to individual platelet or lymphocyte count3-5.

PLR is also an inexpensive, easily calculated, readily available and reproducible biomarker,

which may be useful to be incorporated into risk stratification models in patients undergoing

coronary angiography to identify high-risk patients for targeted intervention.

Prior studies demonstrated the association between PLR and cardiovascular events. Azab

et al showed higher PLR independently predicted 4-year mortality in non-STEMI patients2,

while Osadnik et al demonstrated the predictive value of PLR in patients with stable CAD

undergoing PCI and stent implantation9. Cho et al investigated the prognostic value of PLR and

NLR in patients without STEMI undergoing elective PCI with drug-eluting stents and showed

PLR and NLR, alone and in combination, predicted long-term MACE7. In a population of

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STEMI patients, Temiz et al found PLR independently predicted in-hospital mortality29 and

Ozcan Cetin et al showed PLR predicted in-hospital and long-term MACEs8. In addition, PLR

has also been shown to be associated with slow flow/no-reflow in STEMI patients after PCI11,

severity and complexity of coronary atherosclerosis, and higher SYNTAX score in patients with

acute coronary syndrome undergoing coronary angiography12.

Our study has several limitations. First, the follow-up was not fully complete due to a

specific follow-up period chosen between March to June 2016 for logistical reasons and a large

proportion of rural patients in the BRAVEHEART registry. There is an active process to link the

data with administrative database to obtain further information, which will occur in the medium

term. Second, the values of PLR used in the analysis were computed from samples collected pre-

angiography and more study is warranted to determine the best timing of sample collection for

best estimate of inflammatory status and risk stratification. Third, the prognostic utility of PLR

and the optimal cut-off at 137 were based on this single-center study, which would need to be

further assessed before being deemed applicable in other populations. Fourth, C-reactive protein

was not routinely measured (available in only 18% of the patients followed up) and hence could

not be included in the multivariate model. Fifth, given the exclusion criteria aimed to eliminate

factors that independently affect platelet and lymphocyte counts, the utility of PLR may be

limited to a selective population of patients. Finally, there is a possibility of residual confounding

from variables that were not measured, even after the adjustment for the clinical variables.

In conclusion, high PLR is a strong, independent predictor of long-term all-cause

mortality in patients at high risk of CAD undergoing coronary angiography for various

indications. The assessment of PLR should be considered in other studies addressing prognosis

in this population, which may serve as a useful biomarker in the risk stratification model.

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Acknowledgement: Andrew M. Wilson is supported by grants from the National Heart

Foundation of Australia, Diabetes Australia Research Trust and the Australian Catholic

University (Melbourne, Victoria, Australia). Arul Baradi is supported by an Australian

Government Research Training Program Scholarship and NHMRC Centre of Research

Excellence in Cardiovascular Outcomes Improvement (CRE-COI) PhD Scholarship (Melbourne,

Victoria, Australia).

Disclosures: No disclosures or conflicts of interest

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1. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to

practice. J Am Coll Cardiol 2009;54:2129-2138.

2. Azab B, Shah N, Akerman M, McGinn JT, Jr. Value of platelet/lymphocyte ratio as a

predictor of all-cause mortality after non-ST-elevation myocardial infarction. J Thromb

Thrombolysis 2012;34:326-334.

3. Nikolsky E, Grines CL, Cox DA, Garcia E, Tcheng JE, Sadeghi M, Mehran R, Lansky AJ, Na

Y, Stone GW. Impact of baseline platelet count in patients undergoing primary percutaneous

coronary intervention in acute myocardial infarction (from the CADILLAC trial). Am J Cardiol

2007;99:1055-1061.

4. Ommen SR, Hodge DO, Rodeheffer RJ, McGregor CG, Thomson SP, Gibbons RJ. Predictive

power of the relative lymphocyte concentration in patients with advanced heart failure.

Circulation 1998;97:19-22.

5. Zouridakis EG, Garcia-Moll X, Kaski JC. Usefulness of the blood lymphocyte count in

predicting recurrent instability and death in patients with unstable angina pectoris. Am J Cardiol

2000;86:449-451.

6. Petersen AK, Krumsiek J, Wagele B, Theis FJ, Wichmann HE, Gieger C, Suhre K. On the

hypothesis-free testing of metabolite ratios in genome-wide and metabolome-wide association

studies. BMC Bioinformatics 2012;13:120.

7. Cho KI, Ann SH, Singh GB, Her AY, Shin ES. Combined Usefulness of the Platelet-to-

Lymphocyte Ratio and the Neutrophil-to-Lymphocyte Ratio in Predicting the Long-Term

Adverse Events in Patients Who Have Undergone Percutaneous Coronary Intervention with a

Drug-Eluting Stent. PLoS One 2015;10:e0133934.

12
Page 12 of 21
8. Ozcan Cetin EH, Cetin MS, Aras D, Topaloglu S, Temizhan A, Kisacik HL, Aydogdu S.

Platelet to Lymphocyte Ratio as a Prognostic Marker of In-Hospital and Long-Term Major

Adverse Cardiovascular Events in ST-Segment Elevation Myocardial Infarction. Angiology

2016;67:336-345.

9. Osadnik T, Wasilewski J, Lekston A, Strzelczyk J, Kurek A, Gonera M, Gawlita M, Regula R,

Bujak K, Szygula-Jurkiewicz B, Wiczkowski A, Polonski L. The platelet-to-lymphocyte ratio as

a predictor of all-cause mortality in patients with coronary artery disease undergoing elective

percutaneous coronary intervention and stent implantation. J Saudi Heart Assoc 2015;27:144-

151.

10. Hudzik B, Szkodzinski J, Gorol J, Niedziela J, Lekston A, Gasior M, Polonski L. Platelet-to-

lymphocyte ratio is a marker of poor prognosis in patients with diabetes mellitus and ST-

elevation myocardial infarction. Biomark Med 2015;9:199-207.

11. Kurtul A, Yarlioglues M, Murat SN, Ergun G, Duran M, Kasapkara HA, Demircelik MB,

Cetin M, Ocek AH. Usefulness of the platelet-to-lymphocyte ratio in predicting angiographic

reflow after primary percutaneous coronary intervention in patients with acute ST-segment

elevation myocardial infarction. Am J Cardiol 2014;114:342-347.

12. Kurtul A, Murat SN, Yarlioglues M, Duran M, Ergun G, Acikgoz SK, Demircelik MB, Cetin

M, Akyel A, Kasapkara HA, Ornek E. Association of platelet-to-lymphocyte ratio with severity

and complexity of coronary artery disease in patients with acute coronary syndromes. Am J

Cardiol 2014;114:972-978.

13. Vidwan P, Lee S, Rossi JS, Stouffer GA. Relation of platelet count to bleeding and vascular

complications in patients undergoing coronary angiography. Am J Cardiol 2010;105:1219-1222.

13
Page 13 of 21
14. Ommen SR, Gibbons RJ, Hodge DO, Thomson SP. Usefulness of the lymphocyte

concentration as a prognostic marker in coronary artery disease. Am J Cardiol 1997;79:812-814.

15. Akpek M, Kaya MG, Lam YY, Sahin O, Elcik D, Celik T, Ergin A, Gibson CM. 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;110:621-627.

16. Turak O, Ozcan F, Isleyen A, Tok D, Sokmen E, Buyukkaya E, Aydogdu S, Akpek M, Kaya

MG. Usefulness of the neutrophil-to-lymphocyte ratio to predict bare-metal stent restenosis. Am

J Cardiol 2012;110:1405-1410.

17. Sen N, Afsar B, Ozcan F, Buyukkaya E, Isleyen A, Akcay AB, Yuzgecer H, Kurt M,

Karakas MF, Basar N, Hajro E, Kanbay M. The neutrophil to lymphocyte ratio was associated

with impaired myocardial perfusion and long term adverse outcome in patients with ST-elevated

myocardial infarction undergoing primary coronary intervention. Atherosclerosis 2013;228:203-

210.

18. Duffy BK, Gurm HS, Rajagopal V, Gupta R, Ellis SG, Bhatt DL. Usefulness of an elevated

neutrophil to lymphocyte ratio in predicting long-term mortality after percutaneous coronary

intervention. Am J Cardiol 2006;97:993-996.

19. Nunez J, Nunez E, Bodi V, Sanchis J, Minana G, Mainar L, Santas E, Merlos P, Rumiz E,

Darmofal H, Heatta AM, Llacer A. Usefulness of the neutrophil to lymphocyte ratio in

predicting long-term mortality in ST segment elevation myocardial infarction. Am J Cardiol

2008;101:747-752.

20. Park JJ, Jang HJ, Oh IY, Yoon CH, Suh JW, Cho YS, Youn TJ, Cho GY, Chae IH, Choi DJ.

Prognostic value of neutrophil to lymphocyte ratio in patients presenting with ST-elevation

14
Page 14 of 21
myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol

2013;111:636-642.

21. Krenn-Pilko S, Langsenlehner U, Thurner EM, Stojakovic T, Pichler M, Gerger A, Kapp KS,

Langsenlehner T. The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis

in breast cancer patients. Br J Cancer 2014;110:2524-2530.

22. Templeton AJ, Ace O, McNamara MG, Al-Mubarak M, Vera-Badillo FE, Hermanns T,

Seruga B, Ocana A, Tannock IF, Amir E. Prognostic role of platelet to lymphocyte ratio in solid

tumors: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev

2014;23:1204-1212.

23. Furman MI, Benoit SE, Barnard MR, Valeri CR, Borbone ML, Becker RC, Hechtman HB,

Michelson AD. Increased platelet reactivity and circulating monocyte-platelet aggregates in

patients with stable coronary artery disease. J Am Coll Cardiol 1998;31:352-358.

24. Ault KA, Cannon CP, Mitchell J, McCahan J, Tracy RP, Novotny WF, Reimann JD,

Braunwald E. Platelet activation in patients after an acute coronary syndrome: results from the

TIMI-12 trial. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1999;33:634-639.

25. Tsiara S, Elisaf M, Jagroop IA, Mikhailidis DP. Platelets as predictors of vascular risk: is

there a practical index of platelet activity? Clin Appl Thromb Hemost 2003;9:177-190.

26. Jennings LK. Mechanisms of platelet activation: need for new strategies to protect against

platelet-mediated atherothrombosis. Thromb Haemost 2009;102:248-257.

27. Thomson SP, McMahon LJ, Nugent CA. Endogenous cortisol: a regulator of the number of

lymphocytes in peripheral blood. Clin Immunol Immunopathol 1980;17:506-514.

28. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med

2003;348:138-150.

15
Page 15 of 21
29. Temiz A, Gazi E, Gungor O, Barutcu A, Altun B, Bekler A, Binnetoglu E, Sen H, Gunes F,

Gazi S. Platelet/lymphocyte ratio and risk of in-hospital mortality in patients with ST-elevated

myocardial infarction. Med Sci Monit 2014;20:660-665.

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Figure legends

Figure 1. Diagnostic characteristics of PLR for prediction of all-cause mortality.

The ROC curve analysis was performed to determine the optimal cut-off value of PLR to predict

all-cause mortality. The optimal cut-off value of PLR was calculated to be at 137. The area under

the curve was 0.61 (95% CI 0.53 to 0.70, p = 0.010), with sensitivity of 62%, specificity of 63%,

positive predictive value of 15%, negative predictive value of 94% and diagnostic accuracy of

63%. CI = confidence interval; PLR = platelet-to-lymphocyte ratio; ROC = receiver-operating

characteristic.

Figure 2. Kaplan-Meier analysis showing cumulative hazards for all-cause mortality according to

the PLR tertiles.

Solid line represents T1, dashed line represents T2, dotted line represents T3. Log-rank test was

used to compute the p-values. PLR = platelet-to-lymphocyte ratio; T1 = Tertile 1; T2 = Tertile 2;

T3 = Tertile 3.

Figure 3. Kaplan-Meier analysis showing cumulative hazards for all-cause mortality in patients

with PLR <137 versus PLR ≥137.

Orange line represents PLR ≥137 and navy line represents PLR <137. Log-rank test was used to

compute the p-values. PLR = platelet-to-lymphocyte ratio.

17
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Table 1. Baseline clinical and biochemical characteristics of the study population based on

platelet-to-lymphocyte ratio tertiles

Variable Total Tertile 1 Tertile 2 Tertile 3 p-

(n=514) (n=171) (n=171) (n=172) value
Age (years) 64 ± 11 63 ± 11 62 ± 10 65 ± 12 0.007
Age over 65 265 (52%) 82 82 101 0.07
(48%) (48%) (59%)
Male gender 354 (69%) 121 110 123 0.29
(71%) (64%) (72%)
Body mass index (kg/m2) 29.7 ± 5.6 30.4 ± 30.0 ± 28.7 ± 0.008
6.0 5.5 5.1
Systolic blood pressure (mmHg) 138 ± 22 140 ± 138 ± 136 ± 0.26
22 22 23
Diastolic blood pressure (mmHg) 82 ± 12 82 ± 12 83 ± 12 80 ± 11 0.09
Hypertension* 439 (85%) 151 142 146 0.38
(88%) (83%) (85%)
Diabetes Mellitus** 149 (29%) 69 40 40 <0.00
(40%) (24%) (23%) 1
Hypercholesterolemia† 436 (85%) 145 147 144 0.85
(85%) (86%) (84%)
Smoker 78 (15%) 35 22 21 0.06
(20%) (13%) (12%)
Hemoglobin (g/L) 134 ± 15 135 ± 135 ± 131 ± 0.042
15 14 17
White cell count (x109/L) 7.4 ± 2.1 7.9 ± 7.2 ± 6.9 ± <0.00
2.2 2.1 2.1 1
Lymphocyte (x109/L) 2.0 ± 0.7 2.5 ± 2.0 ± 1.5 ± <0.00
0.7 0.5 0.4 1
Platelet (x109/L) 246 ± 73 209 ± 248 ± 281 ± <0.00
54 54 87 1
Platelet-to-lymphocyte ratio 134 ± 57 85 ± 16 124 ± 193 ± <0.00
11 58 1
Creatinine (μmol/L) 74 ± 20 74 ± 18 72 ± 22 76 ± 20 0.07
Estimated glomerular filtration rate 92 ± 25 91 ± 25 94 ± 25 90 ± 26 0.13
(ml/min/1.73m2)
Hemoglobin A1c (%) 6.2 ± 1.2 6.4 ± 6.1 ± 5.9 ± <0.00
1.4 1.2 0.9 1
Acute myocardial infarction at admission 99 (19%) 27 40 32 0.20
(16%) (23%) (19%)
Coronary artery disease‡ 364 (71%) 124 112 128 0.16
(73%) (66%) (74%)

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Continuous data are presented as mean ± standard deviation. Categorical data are presented as

number (%). *Hypertension was defined as a previous diagnosis or current use of anti-

hypertensive medications. **Diabetes was defined as a previous diagnosis or current use of anti-

diabetic medications. †Hypercholesterolemia was defined as a previous diagnosis or current use

of cholesterol medications. ‡Coronary artery disease was defined by the presence of 50% or

more stenosis in at least 1 of the main coronary arteries or previous percutaneous coronary

intervention for a stenotic coronary artery.

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Table 2. Multivariate Cox analysis of predictors of all-cause mortality in all patients undergoing

coronary angiography

Hazard Ratio 95% Confidence p-value

Interval
Model A – Platelet-to-lymphocyte ratio as a continuous variable
Age, per additional year 1.07 1.03~1.11 0.001
Diabetes mellitus 1.92 1.01~3.64 0.046
Platelet-to-lymphocyte ratio 1.06 1.01~1.10 0.009
(per 10-unit increase)
Model B – Stratified to platelet-to-lymphocyte ratio tertile groups
Age, per additional year 1.07 1.03~1.11 0.001
Diabetes mellitus 1.96 1.03~3.73 0.041
Platelet-to-lymphocyte ratio
Tertile 1 (≤106) 1.00 Reference
Tertile 2 (106.1~145) 1.30 0.51~3.30 0.586
Tertile 3 (>145) 2.52 1.18~5.39 0.017
Model C – Platelet-to-lymphocyte ratio <137 vs. ≥137
Age, per additional year 1.07 1.03~1.11 0.001
Diabetes mellitus 1.90 1.01~3.60 0.047
Platelet-to-lymphocyte ratio ≥137 2.25 1.21~4.20 0.011

Adjusted for male gender, body mass index, hypertension, hypercholesterolemia, smoking and

coronary artery disease.

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Table 3. Multivariate Cox analysis of predictors of all-cause mortality in patients without acute

myocardial infarction undergoing coronary angiography

Hazard Ratio 95% Confidence p-value

Interval
Model A – Platelet-to-lymphocyte ratio as a continuous variable
Age, per additional year 1.05 1.01~1.09 0.022
Platelet-to-lymphocyte ratio 1.07 1.02~1.12 0.004
(per 10-unit increase)
Model B – Stratified to Platelet-to-lymphocyte ratio tertile groups
Age, per additional year 1.05 1.01~1.11 0.015
Platelet-to-lymphocyte ratio
Tertile 1 (≤106) 1.00 Reference
Tertile 2 (106.1~145) 1.21 0.43~3.37 0.717
Tertile 3 (>145) 2.57 1.13~5.84 0.024
Model C – Platelet-to-lymphocyte ratio <137 vs. ≥137
Age, per additional year 1.05 1.01~1.10 0.013
Platelet-to-lymphocyte ratio ≥137 2.41 1.21~4.80 0.012
Adjusted for male gender, body mass index, hypertension, diabetes, hypercholesterolemia,

smoking and coronary artery disease.

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