Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in patients with acute heart failure (HF) and neoplastic diseases. We investigated the association between NLR and mortality or cardiac transplantation in a retrospective cohort of 527 patients presented to the Cleveland Clinic for evaluation of advanced HF therapy options from 2007 to 2010. Patients were divided according to low, intermediate, and high tertiles of NLR and were followed longitudinally for time to all-cause mortality or heart transplantation (primary outcome). The median NLR was 3.9 (interquartile range 2.5 to 6.5). In univariate analysis, intermediate and highest tertiles of NLR had a higher risk than the lowest tertile for the primary outcome and all-causes mortality. Compared with the lowest tertile, there was no difference in the risk of heart transplantation for intermediate and high tertiles. In multivariate analysis, compared with the lowest tertile, the intermediate and high NLR tertiles remained significantly associated with the primary outcome (hazard ratio [HR] = 1.61, 95% confidence interval [CI] 1.10 to 2.37 and HR = 1.55, 95% CI 1.02 to 2.36, respectively) and all-cause mortality (HR = 1.83, 95% CI 1.07 to 3.14 and HR = 2.16, 95% CI 1.21 to 3.83, respectively). In conclusion, elevated NLR is associated with increased mortality or heart transplantation risk in patients with advanced HF.
Highlights
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Higher NLR portends increased risk of mortality or heart transplantation in patients with advanced heart failure.
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This association was mainly driven by higher mortality risk, as we did not find association between NLR and heart transplantation after multivariate adjustments.
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It appears that NLR is more likely a risk marker than the altered composition of leukocytes being a risk mediator for advanced heart failure.
Lymphocytopenia has long been associated with poor prognosis in heart failure (HF). Several studies over the past few decades have demonstrated the potential of neutrophil-to-lymphocyte ratio (NLR), a widely available hematologic marker of oxidative stress damage, to serve as a good prognostic marker of mortality in cardiac and noncardiac diseases. In this study, we evaluated the association between NLR and future risk of mortality or cardiac transplantation in a large contemporary cohort of patients with advanced HF.
Methods
We analyzed 549 consecutive patients presented to the Cleveland Clinic (Cleveland, Ohio) from 2007 to 2010 for evaluation of advanced HF therapies and consideration for heart transplantation or mechanical circulatory assist devices. Electronic medical records were used to obtain demographic variables (age, gender, and race), clinical variables, laboratory values, and medications. Among this cohort, 527 patients had documented values of NLR within the time frame and clinical stability to complete the comprehensive evaluation for advanced HF therapeutics and were included in this study. Mortality data were obtained from social security death index (until 2012) and timing of death and heart transplantation were confirmed by review of the electronic medical records. The construction of the database was conducted by an independent researcher who was not involved in the care of patients. Data were collected retrospectively and the study was approved by the Institutional Review Board of the Cleveland Clinic.
NLR was calculated as the ratio between neutrophil count and lymphocyte count obtained at the time of evaluation. Participants were categorized in NLR tertiles low (<3.0), intermediate (3.0 to 5.4), and high (>5.4). The primary outcome was a composite of all-cause mortality or heart transplantation. Information on heart transplantation was extracted from the electronic records.
Continuous variables were described as mean and SD or median with interquartile range. Categorical variables were expressed as frequencies and percentages. Continuous variables were compared among NLR tertiles with the analysis of variance or Kruskal-Wallis tests; categorical variables were compared with the chi-square test. The Kaplan-Meier method was used to evaluate survival or freedom from events, and the log-rank test was used to evaluate differences among NLR tertiles. Univariate and multivariate Cox regression models were used to assess the association between tertiles of NLR and the primary outcome or its components. We reported crude and adjusted hazard ratios (HRs) with their 95% confidence intervals (CIs). Variables with p <0.2 in univariate analysis were considered candidates to enter into the multivariate model along with age, gender, and race. The variable mechanical circulatory assist device was analyzed as a time-dependent variable. Analyses were conducted in STATA version 11.0 (StataCorp LP, College Station, Texas).
Results
Of the 527 patients, 176, 177, and 174 patients were in the lowest, intermediate, and higher NLR tertile, respectively. Baseline characteristics of the patients across NLR tertiles are listed in Table 1 . Overall, NLR correlated directly with B-type natriuretic peptide (r = 0.14, p <0.01). There was no correlation between NLR and left ventricular ejection fraction, peak oxygen consumption, and hemodynamic variables. The distribution of the logarithm of NLR is presented in Figure 1 , stratified according to gender (mean ± SD, NLR men 5.9 ± 6.3 vs women 5.5 ± 8.4, p = 0.6).
| Neutrophil-to-Lymphocyte ratio | Tertiles | p Value | ||
|---|---|---|---|---|
| Variable | Low (n=176) | Intermediate (n=177) | High (n= 174) | |
| Age (years) | 53 (43-61) | 59 (51-64) | 57 (47-64) | <0.01 |
| Male | 113 (64%) | 136 (77%) | 134 (77%) | <0.01 |
| Black | 42 (25.4%) | 18 (11.2) | 20 (12.7) | <0.01 |
| Smoke | 47 (27%) | 35 (20%) | 32 (18 %) | 0.13 |
| Diabetes mellitus | 38(22%) | 53(30%) | 46 (26%) | 0.19 |
| Hypertension | 60 (34%) | 81(46%) | 77 (44%) | 0.05 |
| Dyslipidemia | 74(42%) | 86(49%) | 64 (37%) | 0.07 |
| Non-ischemic heart failure | 113 (65%) | 97 (55.4%) | 100 (57.8%) | 0.20 |
| Chronic obstructive pulmonary disease | 15(9%) | 16 (9%) | 14(8%) | 0.98 |
| Coronary Artery Disease | 65 (37%) | 77 (44%) | 84 (48%) | 0.10 |
| Stroke | 13 (7%) | 21 (12%) | 19 (11%) | 0.33 |
| Atrial Fibrillation | 61(35%) | 67(38%) | 66 (38%) | 0.76 |
| Ventricular Assist Device | 34 (19%) | 58 (33%) | 60 (35%) | <0.01 |
| Creatinine (mg/dL) | 1.1 (0.9-1.4) | 1.2 (1.0-1.5) | 1.3 (1.0-1.8) | <0.01 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 85 (63-111) | 81 (56-112) | 68 (48-100) | <0.01 |
| Total Protein (g/dL) | 6.9 (6.3-7.4) | 6.7 (6.2-7.3) | 6.2 (5.3-6.9) | <0.01 |
| Albumin (g/dL) | 4.0 (3.6-4.4) | 4.0 (3.4- 4.4) | 3.4 (2.8-3.9) | <0.01 |
| Bilirubin (mg/dL) | 0.8 (0.5-1.2) | 0.8 (0.5-1.5) | 1.1 (0.7-1.8) | <0.01 |
| Blood Urea Nitrogen (mg/dL) | 20 (15-40) | 24 (19-33) | 29 (22-38) | <0.01 |
| Sodium (mEq/L) | 136 (134-139) | 136 (134-139) | 135(132-138) | <0.01 |
| B-type Natriuretic Peptide (pg/mL) | 454 (102-804) | 498 (225-956) | 619 (244-1224) | <0.01 |
| Platelets (10 3 /μL) | 193 (155-244) | 194 (164-231) | 173 (127-223) | <0.01 |
| Platelet -to-lymphocyte ratio | 104 (77-134) | 157 (118-211) | 222 (152-335) | <0.01 |
| Mean Platelet Volume (fL) | 10.5 (9.9-11.0) | 10.4 (9.8-11.2) | 10.2 (9.7-11.0) | 0.21 |
| Neutrophil-to-lymphocyte ratio | 2.1 (1.6-2.5) | 3.9 (3.4-4.8) | 8.1 (6.5-12.4) | <0.01 |
| Aspirin | 94 (53%) | 109 (62%) | 94 (54%) | 0.20 |
| Beta-blocker | 118 (67%) | 130 (74%) | 87 (50%) | <0.01 |
| Angiotensin-converting enzyme Inhibitors | 101 (57%) | 80 (46%) | 59 (34%) | <0.01 |
| Clopidogrel | 29(17%) | 27(15%) | 22 (13%) | 0.60 |
| Spironolactone | 85(48%) | 90 (52%) | 67 (39%) | 0.05 |
| Hydralazine | 33 (19%) | 50 (28%) | 50 (29%) | 0.05 |
| Nitrates | 46 (26%) | 53 (30%) | 56 (32%) | 0.45 |
| Angiotensin II receptor blocker | 21(12%) | 24 (14%) | 16 (9%) | 0.43 |
| Warfarin | 64 (36%) | 63 (36%) | 62 (36%) | 0.99 |
Over a median follow-up period of 11.3 (interquartile range 3.4 to 21.1) months, the primary outcome occurred in 263 patients (50%), 121 patients were transplanted (23%), and 158 patients died during follow-up (30%). In univariate analysis, NLR was associated with the primary end point (p <0.01, Figure 2 ). In comparison to the lowest tertile, the intermediate and high tertiles of NLR had higher risk for the primary outcome. In multivariate analysis, and compared with the lowest tertile, the intermediate and highest NLR tertiles were associated with the primary outcome (HR = 1.61, 95% CI 1.10 to 2.37 and HR = 1.55, 95% CI 1.02 to 2.36, respectively; Table 2 ). Compared with the lowest tertile, the intermediate and highest tertiles of NLR had increased risk of all-cause mortality in univariate analysis ( Figure 3 ). In multivariate analysis and compared with the lowest tertile, the intermediate and high NLR tertiles remained significantly associated with all-causes mortality (HR = 1.83, 95% CI 1.07 to 3.14 and HR = 2.16, 95% CI 1.21 to 3.83, respectively; Table 2 ). No association between NLR and heart transplantation was observed in univariate analysis or multivariate analysis ( Table 2 , Figure 4 ). We did not find an association between lymphocyte or neutrophil counts with all-cause mortality in models using the same set of confounders of our primary analyses ( Table 3 ).
| Outcomes | NLR Tertiles | Crude HR (95% CI) | p value | Adjusted HR (95% CI) | p value |
|---|---|---|---|---|---|
| All-cause Mortality or Heart ∗ Transplantation | Higher | 1.93 (1.42-2.63) | <0.01 | 1.55 (1.02-2.36) | 0.04 |
| Intermediate | 1.42 (1.03-1.96) | 0.03 | 1.61 (1.10-2.37) | 0.02 | |
| Lower | 1 | — | 1 | — | |
| All-cause Mortality † | Higher | 2.57 (1.72-3.85) | <0.01 | 2.16 (1.21-3.83) | <0.01 |
| Intermediate | 1.56 (1.01-2.40) | 0.04 | 1.83 (1.07-3.14) | 0.03 | |
| Lower | 1 | — | 1 | — | |
| Heart Transplantation ‡ | Higher | 1.05 (0.66-1.66) | 0.84 | 0.80 (0.47-1.43) | 0.43 |
| Intermediate | 1.15 (0.74-1.76) | 0.54 | 1.10 (0.68-1.84) | 0.71 | |
| Lower | 1 | — | 1 | — |
∗ Adjusted for: Age, sex, black race, cigarette smoker, diabetes, coronary artery disease, atrial fibrillation, ventricular assist device, albumin, bilirubin, blood urea nitrogen, sodium, brain natriuretic peptide, platelets, aspirin, beta-blocker, angiotensin-converting enzyme inhibitors and hydralazine.
† Adjusted for: Age, sex, black race, diabetes, hypertension, No ischemic failure, chronic obstructive pulmonary disease, coronary artery disease, stroke, atrial fibrillation, ventricular assist device, creatinine, estimated glomerular filtration rate albumin, blood urea nitrogen, brain natriuretic peptide, platelets and beta-blocker.
‡ Adjusted for: Age, black race, cigarette smoker, hypertension, dyslipidemia, no ischemic failure, chronic obstructive pulmonary disease, stroke, ventricular assist device, albumin, sodium, mean platelet volume, aspirin, beta-blocker, angiotensin-converting enzyme inhibitors and hydralazine. Model stratified by gender.
| Outcomes | Tertiles | Neutrophil Crude HR (95% CI) | Neutrophil Adjusted HR (95% CI) | p value | Lymphocyte Crude HR (95% CI) | Lymphocyte Adjusted HR (95% CI) | p value |
|---|---|---|---|---|---|---|---|
| All-cause Mortality or Heart Transplantation ∗ | Higher | 1.15 (0.83-1.60) | 1.10 (0.74-1.62) | 0.65 | 0.45 (0.33-0.62) | 0.53 (0.35-0.81) | <0.01 |
| Intermediate | 1.42 (1.05-1.94) | 1.47 (1.04-2.08) | 0.03 | 0.57 (0.42-0.77) | 0.63 (0.44-0.90) | <0.01 | |
| Lower | 1 | 1 | — | 1 | 1 | — | |
| All-cause Mortality † | Higher | 1.44 (0.97-2.14) | 1.39 (0.84-2.31) | 0.20 | 0.59 (0.39-0.88) | 0.96 (0.54-1.69) | 0.88 |
| Intermediate | 1.16 (0.78-1.75) | 1.05 (0.65-1.69) | 0.85 | 0.68 (0.46-0.99) | 0.96 (0.60-1.55) | 0.87 | |
| Lower | 1 | 1 | — | 1 | 1 | — | |
| Heart Transplantation ‡ | Higher | 0.67 (0.38-1.17) | 0.56 (0.31-1.00) | 0.05 | 0.46 (0.28-0.76) | 0.45 (0.26-0.80) | <0.01 |
| Intermediate | 1.59 (1.03- 2.47) | 1.64 (1.04-2.58) | 0.03 | 0.60 (0.38-0.94) | 0.64 (0.33-0.87) | 0.01 | |
| Lower | 1 | 1 | — | 1 | 1 | — |
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