Neutrophil-to-Lymphocyte Ratios in Patients Undergoing Aortic Valve Replacement: The PARTNER Trials and Registries.

Background The neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic inflammation has been associated with worse prognosis in several chronic disease states, including heart failure. However, few data exist on the prognostic impact of elevated baseline NLR or change in NLR levels during follow-up in patients undergoing transcatheter or surgical aortic valve replacement (TAVR or SAVR) for aortic stenosis. Methods and Results NLR was available in 5881 patients with severe aortic stenosis receiving TAVR or SAVR in PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials/registries (median [Q1, Q3] NLR, 3.30 [2.40, 4.90]); mean NLR, 4.10; range, 0.5-24.9) and was evaluated as continuous variable and categorical tertiles (low: NLR ≤2.70, n=1963; intermediate: NLR 2.70-4.20, n=1958; high: NLR ≥4.20, n=1960). No patients had known baseline infection. High baseline NLR was associated with increased risk of death or rehospitalization at 3 years (58.4% versus 41.0%; adjusted hazard ratio [aHR], 1.39; 95% CI, 1.18-1.63; P<0.0001) compared with those with low NLR, irrespective of treatment modality. In both patients treated with TAVR and patients treated with SAVR, NLR decreased between baseline and 2 years. A 1-unit observed decrease in NLR between baseline and 1 year was associated with lower risk of death or rehospitalization between 1 year and 3 years (aHR, 0.86; 95% CI, 0.82-0.89; P<0.0001). Conclusions Elevated baseline NLR was independently associated with increased subsequent mortality and rehospitalization after TAVR or SAVR. The observed decrease in NLR after TAVR or SAVR was associated with improved outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00530894, NCT0134313, NCT02184442, NCT03225001, NCT0322141.

aortic stenosis

aortic valve replacement

neutrophil‐to‐lymphocyte ratio

New York Heart Association

Placement of Aortic Transcatheter Valves

Renin‐Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation

surgical aortic valve replacement

transcatheter aortic valve replacement

Clinical Perspective

What Is New?

In the PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials or registries of 5881 patients treated with transcatheter aortic valve replacement or surgical aortic valve replacement, elevated preprocedure neutrophil‐to‐lymphocyte ratio was associated with increased risk of mortality and rehospitalization.

Decrease in neutrophil‐to‐lymphocyte ratio during follow‐up was associated with lower risk of subsequent events in both patients treated with surgical aortic valve replacement and patients treated with transcatheter aortic valve replacement.

What Are the Clinical Implications?

Future studies are needed to determine whether changes in neutrophil‐to‐lymphocyte ratio after transcatheter aortic valve replacement or surgical aortic valve replacement may help inform prognosis and symptom relief and whether strategies targeting the pathobiology underlying elevated neutrophil‐to‐lymphocyte ratio will improve patient outcomes.

Systemic inflammation and heart failure (HF) are believed to be strongly interconnected and potentially synergistic to each other. While inflammatory mediators from peripheral tissues can influence the development and progression of HF, mechanical overload and shear stress in HF may cause the release of proinflammatory cytokines from the myocardium, which in addition to having direct local effects, may cause remodeling in organs distal from the heart as HF progresses. Systemic inflammation also appears to contribute to frailty, which might explain why the prevalence of frailty is high in patients with HF.

The neutrophil‐to‐lymphocyte ratio (NLR) is an index of the innate (ie, neutrophils) and adaptive (ie, lymphocytes) immune pathways that has been proposed to be a better marker of systemic inflammation compared with total white blood count or the individual components of the white blood count. , , Elevated NLR has been associated with worse outcomes in patients with cancer and cardiovascular diseases, including acute and chronic HF.

Although an association has been observed for NLR and prognosis among patients with HF, few data exist on the prognostic implications of NLR for patients with severe aortic stenosis (AS) undergoing aortic valve replacement (AVR). Accordingly, we examined whether NLR was associated with clinical and functional outcomes following transcatheter AVR (TAVR) or surgical AVR (SAVR) for severe AS; if treatment with SAVR or TAVR differentially affects NLR levels at follow‐up; and whether change in NLR after AVR is associated with clinical and functional outcomes in a large, individual patient‐level, pooled database of the PARTNER (Placement of Aortic Transcatheter Valves) trials and registries.

Methods

Study Design and Patient Population

We conducted a cohort study of all patients included in the PARTNER trials and registries. The designs of these trials and registries have been previously reported. , , , Specifically, the patient study population included patients from PARTNER IA (operable high‐risk randomized cohort and continued access registries; NCT00530894); PARTNER IB (inoperable high‐risk randomized cohort, randomized continued access, and nonrandomized continued access registries; NCT00530894); PARTNER IIA (operable intermediate‐risk randomized cohort; NCT01314313), PARTNER IIB (inoperable randomized SAPIEN XT cohort and nested registries of inoperable transapical, transaortic, 29‐mm transfemoral, continued access registries and valve‐in‐valve registries; NCT02184442, NCT03225001) and PARTNER II (SAPIEN 3 high‐risk/inoperable observational cohort; NCT03222141). The pooled patient populations included in the study are itemized by trials and registries in Figure S1. Patients randomized to medical therapy in PARTNER IB were excluded. The population was analyzed in an as‐treated fashion with respect to TAVR and SAVR. In all cohorts, patients had severe AS, defined as an aortic valve area <0.8 cm2 (or indexed aortic valve area <0.5 cm2/m2) and either resting or inducible mean gradient >40 mm Hg or peak jet velocity >4 m/s. All patients were symptomatic from their AS with New York Heart Association (NYHA) functional class II or higher symptoms. Key exclusion criteria for all cohorts included baseline active infection, serum creatinine >3 mg/dL or renal replacement therapy, acute myocardial infarction, a congenitally bicuspid aortic valve, severe aortic regurgitation, left ventricular ejection fraction (LVEF) <20%, and estimated life expectancy of <2 years. The study was conducted according to the Declaration of Helsinki. Informed consent was required before trial and registry enrollment, and the study was approved by individual site institutional review boards. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Clinical Data and End Points

Clinical data and transthoracic echocardiograms were obtained at baseline, hospital discharge, 30 days, 1 year, and 2 years. NLR was measured at baseline (preprocedure), discharge, 30 days, and 1‐year and 2‐year follow‐up. All echocardiograms were interpreted by independent core laboratories. The primary end point of this analysis was death or rehospitalization. Rehospitalization was defined as the need for repeat hospitalization because of aortic stenosis (ie, heart failure, angina, or syncope) or for complications related to the valve procedure (ie, infection, stroke, renal failure, vascular complication). Outcomes were adjudicated by an independent clinical events committee in each individual trial. NLR was calculated as the ratio of neutrophil count to lymphocyte count. NLR was evaluated both as a continuous log‐transformed variable and tertiles (low <2.70), intermediate (2.70–4.20), or high (≥4.20) since there is no universal cutoff for NLR as an inflammatory marker.

Statistical Analysis

Patients were grouped according to NLR tertiles (T1‐T3) to compare demographic, clinical, echocardiographic, and procedural characteristics. Baseline characteristics were summarized as means and SDs or medians and interquartile ranges for continuous measures and proportions for categorical variables. Continuous variables are presented as means and SDs and compared using analysis of variance. Categorical variables are shown as counts and frequencies and compared using the chi‐square or Fisher’s exact test. For time‐to‐first‐event analyses, event rates were estimated by the Kaplan‐Meier method and compared with Cox regression. Multivariable Cox proportional hazards models were adjusted for the following predefined clinically pertinent covariates and baseline characteristics that were significantly different between the NLR tertile groups: age, sex, diabetes, body mass index, chronic obstructive pulmonary disease, renal insufficiency (serum creatinine ≥2 mg/dL), previous or current cancer, baseline hemoglobin, previous stroke or transient ischemic attack, major arrhythmia, NYHA class III or IV, LVEF, Society of Thoracic Surgeons risk score, access (transfemoral versus transthoracic), coronary artery disease, peripheral arterial disease, LVEF, left ventricular mass index, left ventricular end diastolic diameter, moderate to severe mitral regurgitation, B‐type natriuretic peptide, randomized treatment, and study cohort. Data on tricuspid regurgitation and frailty were uniformly available only in the P2 cohort, in which a sensitivity analysis was performed adjusting for moderate to severe tricuspid regurgitation and frailty as reflected by gait speed (15‐foot walk test), in addition to the above‐mentioned covariates. Because the presence of cancer and immunosuppressive treatment might affect NLR, a second sensitivity analysis was performed that excluded patients with current cancer or previous or current immunosuppressive treatment. These patients were infrequent (n=106 with current cancer and n=149 with previous or current immunosuppressive therapy) and were included in the primary analysis given that the distribution of NLR in these patients was similar to that of the overall population (Figure S2A through S2C). All multivariable models were stratified by study.

Interaction terms were included to assess whether the impact of NLR differed in SAVR versus TAVR, in patients with and without coronary artery disease, and without diabetes, with obesity (body mass index ≥30 versus <30) and at high versus intermediate or low surgical risk. Nonlinear relationships between NLR and the risk of clinical outcomes were explored using penalized splines with 2 degrees of freedom. NLRs were right skewed and normalized with a logarithmic transformation when analyzed as a continuous variable. The change in NLR levels over time was normally distributed.

ANCOVA was performed in the randomized cohorts to compare mean changes in NLR from baseline to follow‐up between TAVR and SAVR, adjusted for baseline NLR values. Changes in NLR over time in the overall cohort were analyzed using a linear mixed‐effects model, adjusting for study using a random effect. The association of change in NLR at several time points (baseline, 30 days, and 1 year) with clinical outcomes at 2 years was analyzed using a landmark approach. The landmark analysis refers to designating a time point occurring during the follow‐up period known as the landmark time, which in the present analysis was the change in NLR levels between baseline and each follow‐up time point and excluding events occurring before the landmark time.

Associations between change in NLR levels from baseline to follow‐up time points (follow‐up value–baseline value) with changes in the Kansas City Cardiomyopathy Questionnaire, 6‐minute walk distance, left ventricular function (LVEF), and mean aortic gradients were assessed by ANCOVA regression models, adjusting for the baseline values of those variables with the assumption of equal variance.

All P values are 2‐tailed, and P<0.05 was considered significant for all analyses. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC).

Results

Study Population and Baseline Characteristics

Out of a total of 8530 patients, baseline NLR was available in 5881 patients (68.9%), of whom 2446 were from the PARTNER I trial, 3022 were from the PARTNER 2 Sapien XT, and 413 were from Partner II Sapien 3 cohorts (Figure S1). Most patients underwent TAVR (n=4 840, 82.3%) as opposed to SAVR (n=1041, 17.7%). The distribution of NLR was nonnormal and right‐skewed (Figure S2A) with a median [Q1, Q3] of 3.30 [2.40, 4.90], ranging from 0.5 to 24.9. Table 1 shows various baseline clinical and echocardiographic characteristics of patients stratified by NLR tertiles (high [≥4.20], intermediate [2.70–4.20], and low [≤2.70]). Higher NLR was associated with male sex, more comorbidities, higher Society of Thoracic Surgeons risk score, and worse left ventricular function. Patients with higher NLR were more often treated with diuretics, antiarrhythmics, and anticoagulants (Table S1). Higher NLR was also associated with longer hospital stay, larger prosthesis size (TAVR arm), and longer aortic cross‐clamp time (SAVR arm) (Table S2).

Table 1

Baseline Clinical and Echocardiographic Characteristics of Patients by Tertiles of NLR

	NLR Tertile			Overall P value
	Low (≤2.7) n=1963	Intermediate (2.7–4.2) n=1958	High (≥4.2) n=1960
Clinical characteristics
Age, y	83.1 (7.7)	83.1 (7.8)	82.8 (7.5)	0.43
Male sex	48.0 (942/1963)	57.9 (1134/1958)	61.0 (1196/1960)	<0.0001
Race
White	92.1 (1770/1922)	94.6 (1819/1922)	95.5 (1840/1927)	<0.0001
Black or African American	3.8 (73/1922)	1.8 (35/1922)	1.1 (22/1927)	<0.0001
Body mass index, kg/m2	27.7 (6.3)	27.6 (6.2)	27.5 (6.5)	0.55
Diabetes	34.5 (677/1961)	36.7 (718/1958)	36.9 (723/1960)	0.23
Insulin dependent	16.8 (329/1957)	18.1 (353/1953)	20.3 (396/1954)	0.02
Non–insulin dependent	17.6 (344/1957)	18.4 (360/1953)	16.4 (321/1954)	0.25
Previous or current smoker	46.5 (911/1961)	51.2 (1002/1958)	53.4 (1047/1960)	<0.0001
Previous smoker	44.9 (550/1225)	51.1 (587/1149)	52.7 (559/1061)	0.0004
Current smoker	2.6 (32/1225)	2.6 (30/1149)	2.3 (24/1061)	0.83
Renal insufficiency (SCr ≥2 mg/dL)	8.3 (162/1961)	11.5 (224/1956)	16.2 (317/1960)	<0.0001
Liver disease	2.4 (48/1961)	2.9 (56/1957)	3.1 (61/1957)	0.44
Previous or current immunosuppressive therapy	4.5 (36/800)	6.7 (47/703)	12.0 (66/551)	<0.0001
Previous cancer	26.9 (330/1225)	31.2 (358/1149)	32.0 (339/1061)	0.02
Current cancer	2.1 (26/1225)	2.9 (33/1149)	4.4 (47/1061)	0.006
Anemia	19.1 (234/1225)	22.0 (253/1149)	27.0 (286/1061)	<0.0001
Thrombocytopenia	5.1 (62/1225)	4.3 (49/1149)	6.4 (68/1061)	0.07
Coagulopathy	2.0 (39/1960)	1.5 (29/1955)	2.2 (43/1958)	0.24
Previous or current bleeding	11.2 (89/795)	11.6 (81/697)	13.3 (73/548)	0.48
STS‐PROM score	8.5 (4.1)	9.2 (4.5)	10.1 (4.8)	<0.0001
<4	7.6 (150/1962)	4.7 (92/1957)	4.3 (84/1960)	<0.0001
4–8	40.1 (787/1962)	36.6 (717/1957)	28.9 (567/1960)	<0.0001
>8	52.2 (1025/1962)	58.7 (1148/1957)	66.8 (1309/1960)	<0.0001
EuroSCORE I	15.0 (14.0)	17.1 (15.6)	19.0 (16.3)	<0.0001
NYHA functional class
I	0.0 (0/1963)	0.0 (0/1958)	0.2 (3/1960)	0.05
II	13.2 (260/1963)	10.6 (208/1958)	7.4 (145/1960)	<0.0001
III	55.0 (1079/1963)	55.2 (1080/1958)	52.8 (1035/1960)	0.26
IV	31.8 (624/1963)	34.2 (670/1958)	39.6 (777/1960)	<0.0001
Congestive heart failure	90.2 (1770/1962)	91.2 (1783/1955)	92.7 (1816/1959)	0.02
Hypertension	93.1 (1825/1961)	92.8 (1818/1958)	92.3 (1809/1959)	0.67
Dyslipidemia	81.8 (1604/1961)	83.9 (1642/1958)	82.4 (1615/1960)	0.21
Coronary artery disease	76.5 (1500/1960)	76.9 (1506/1958)	79.4 (1557/1960)	0.060
Peripheral arterial disease	34.6 (679/1961)	38.7 (757/1958)	38.4 (752/1959)	0.01
Prior stroke or transient ischemic attack	17.7 (346/1959)	18.0 (352/1956)	17.4 (340/1958)	0.87
Prior endocarditis	0.7 (14/1961)	0.9 (18/1955)	0.7 (14/1957)	0.70
History of atrial fibrillation or flutter	33.1 (406/1225)	39.9 (459/1149)	45.8 (486/1061)	<0.0001
Katz activities of daily living index	5.5 (1.1)	5.4 (1.1)	5.2 (1.3)	<0.0001
Grip strength average grasp	20.0 (9.8)	21.0 (10.2)	20.6 (9.5)	0.06
15‐foot walk, sec	8.4 (4.8)	8.6 (4.9)	10.2 (26.2)	0.009
Serum albumin <3.5 mg/dL	17.0 (229/1348)	19.9 (250/1258)	28.7 (335/1168)	<0.0001
B‐type natriuretic peptide	827.0 (2331.0)	985.9 (2148.8)	1328.9 (2822.5)	<0.0001
Echocardiographic characteristics
AV mean area (cm2)	0.69 (0.22)	0.68 (0.20)	0.67 (0.21)	0.08
AV area index, cm2/m2	0.38 (0.11)	0.37 (0.11)	0.36 (0.11)	0.001
AV peak velocity, cm/s	426.0 (63.7)	425.1 (65.6)	422.6 (65.9)	0.25
AV mean gradient, mm Hg	43.6 (13.6)	43.6 (14.0)	43.3 (14.0)	0.70
AV peak gradient, mm Hg	74.2 (22.1)	74.0 (23.0)	73.2 (22.7)	0.34
LV end diastolic diameter, cm	4.52 (0.76)	4.64 (0.79)	4.67 (0.79)	<0.0001
LV end systolic diameter, cm	3.21 (0.90)	3.35 (0.94)	3.43 (0.95)	<0.0001
LV ejection fraction*	54.4 (12.4)	53.0 (12.7)	51.3 (13.5)	<0.0001
LV mass, g	233.6 (73.0)	243.1 (75.4)	250.9 (77.2)	<0.0001
LV stroke volume * , mL	57.4 (19.2)	59.3 (20.0)	59.7 (20.4)	0.007
LV stroke volume index, mL/m2	31.7 (9.8)	32.3 (9.9)	32.4 (10.3)	0.19
E/A ratio	1.15 (0.72)	1.46 (1.02)	1.31 (0.77)	0.03
E/Eʹ ratio (lateral)	15.1 (8.3)	15.3 (8.2)	15.5 (8.8)	0.67
Left atrial volume index, mL/m2	41.9 (13.8)	43.2 (15.6)	46.2 (17.2)	<0.0001
Aortic regurgitation (moderate/severe)	12.6 (239/1892)	13.4 (256/1904)	13.9 (264/1894)	0.49
Mitral regurgitation (moderate/severe)	20.1 (366/1825)	22.6 (419/1852)	24.3 (449/1850)	0.008
Tricuspid regurgitation (moderate/severe)	15.4 (165/1070)	21.4 (216/1011)	22.0 (204/926)	0.0002
Right ventricular systolic pressure, mm Hg	36.5 (12.6)	39.2 (13.3)	41.1 (14.7)	<0.0001

Values are mean (SD) or % (n/N). AV indicates aortic valve; EuroSCORE, European System for Cardiac Operative Risk Evaluation; LV, left ventricular; NLR, neutrophil‐to‐lymphocyte ratio; NYHA, New York Heart Association; SCr, serum creatinine; and STS‐PROM, Society of Thoracic Surgeons Predicted Risk of Mortality.

Visual or Simpson.

Assessed by Doppler.

Clinical Outcomes

The median [Q1, Q3] duration of follow‐up for the entire cohort was 34 [18, 50] months. Outcomes by NLR tertiles are shown in Figure 1, Table S3, and Table 2. Compared with patients in the lowest NLR tertile, patients in the highest tertile had higher rates of the 3‐year composite end point of death or rehospitalization (58.4% versus 41.0%, adjusted hazard ratio [aHR], 1.39; 95% CI, 1.18–1.63; P<0.0001) as well as the individual end points of death and rehospitalization, separately. The association of NLR with the risk of adverse outcomes remained similar in sensitivity analysis, excluding patients with current cancer or previous or current immunosuppressive therapy (Table S4) or when adjusting for moderate to severe tricuspid regurgitation and gait speed (Table S5). The association between NLR and the risk of adverse outcomes remained significant when NLR was modeled as a continuous log‐linear variable (Figure 2 and Table S6). In spline analysis (Figure 2), the nonlinearity P value of 0.23 was consistent with the linear relationship between NLR and the 3‐year risk of the composite of death or rehospitalization. There were no significant interactions between NLR and treatment modality (TAVR versus SAVR), Society of Thoracic Surgeons risk score >8 versus ≤8, presence of diabetes, coronary artery disease, or obesity with the risk of adverse outcomes at 3 years (Table S7). The association between NLR and the risk of adverse outcomes within each cohort was overall similar to that of the pooled study population (Figure S3). When neutrophils and lymphocytes were analyzed individually as continuous variables, increase in neutrophils and decrease in lymphocytes were independently associated with the risk of adverse outcomes (Table S8).

Figure 1

Kaplan–Meier time‐to‐first‐event analyses by tertiles of neutrophil‐to‐lymphocyte ratio in patients undergoing transcatheter aortic valve replacement or surgical aortic valve replacement.

(A) Death or rehospitalization; (B) death; (C) rehospitalization. HR indicates hazard ratio; and NLR, neutrophil‐to‐lymphocyte ratio.

Table 2

Association Between Baseline NLR and 3‐Year Adverse Outcomes

	Unadjusted HR (95% CI)	P value	Model 1a adjusted HR (95% CI)	P value	Model 1b adjusted HR (95% CI)	P value
Death or rehospitalization
High (NLR ≥4.2) vs low (NLR ≤2.7)	1.47 (1.35–1.59)	<0.0001	1.39 (1.18–1.63)	<0.0001	1.42 (1.20–1.69)	<0.0001
Intermediate (NLR 2.7–4.2) vs low (≤2.7)	0.92 (0.85–1.00)	0.06	1.19 (1.01–1.40)	0.04	1.28 (1.07–1.52)	0.006
All‐cause death
High (NLR ≥4.2) vs low (NLR ≤2.7)	1.60 (1.46–1.76)	<0.0001	1.68 (1.37–2.06)	<0.0001	1.69 (1.36–2.11)	<0.0001
Intermediate (NLR 2.7–4.2) vs Low (≤2.7)	0.88 (0.79–0.97)	0.012	1.26 (1.02–1.55)	0.03	1.36 (1.09–1.69)	0.007
Cardiovascular death
High (NLR ≥4.2) vs low (NLR ≤2.7)	1.55 (1.37–1.75)	<0.0001	1.54 (1.19–1.99)	<0.0001	1.57 (1.18–2.07)	0.002
Intermediate (NLR 2.7–4.2) vs low (NLR ≤2.7)	0.90 (0.79–1.03)	0.12	1.23 (0.94–1.61)	0.12	1.31 (0.99–1.74)	0.06
Rehospitalization
High (NLR ≥4.2) vs low (NLR ≤2.7)	1.37 (1.23–1.53)	<0.0001	1.24 (1.01–1.52)	0.04	1.30 (1.04–1.62)	0.02
Intermediate (NLR 2.7–4.2) vs low (≤2.7)	0.96 (0.85–1.08)	0.46	1.06 (0.86–1.31)	0.59	1.12 (0.89–1.40)	0.34

The following covariates were included in the adjusted model 1a: age, sex, diabetes, body mass index, chronic obstructive pulmonary disease, renal insufficiency (serum creatinine ≥2 mg/dL), previous or current cancer, baseline hemoglobin, serum albumin, previous stroke or transient ischemic attack, atrial fibrillation/flutter, left ventricular ejection fraction, left ventricular end‐diastolic diameter, left ventricular mass, moderate to severe mitral regurgitation, coronary artery disease, peripheral artery disease, New York Heart Association class III or IV, Society of Thoracic Surgeons risk score, access (transfemoral vs transthoracic), randomized treatment, and study cohort. Model 1b was, in addition to the covariates included in model 1a, also adjusted for baseline B‐type natriuretic peptide. HR indicates hazard ratio; and NLR, neutrophil‐to‐lymphocyte ratio.

Figure 2

Kaplan‐Meier time‐to‐first‐event analyses by tertiles of neutrophil‐to‐lymphocyte ratio in patients undergoing transcatheter aortic valve replacement or surgical aortic valve replacement.

(A) Death or rehospitalization; (B) death; (C) rehospitalization. HR indicates hazard ratio; and NLR, neutrophil‐to‐lymphocyte ratio.

Change in NLR After TAVR or SAVR and Clinical Outcomes

NLR increased more immediately following SAVR compared with TAVR (Figure S4) but at 30 days, 1 year, and 2 years, NLR levels decreased to similar levels between TAVR and SAVR. To compare change in NLR between treatments, only the 1726 patients enrolled in either of the randomized cohorts were considered (PARTNER 1A and PARTNER 2A). A total of 950 of 1726 patients (55.0%) in the TAVR arm and 776 of 1726 patients (45.0%) in the SAVR arm had paired measurements of NLR values available and were included in this analysis. The least squares mean change in NLR from baseline to 30 days was 0.2±2.6 in patients treated with TAVR and 0.9±2.6 in patients treated with SAVR (difference between groups −0.5 [−0.7 to −0.3; P<0.0001]). After adjustment including baseline NLR values, an increase of 1 unit in NLR between baseline and 30 days was associated with an increased risk of death or rehospitalization between 30 days and 3 years (Table 3).

Table 3

Landmark Analysis for the Risks of Adverse Outcomes 3 Years After Aortic Valve Replacement by Change in NLR at Various Time Points

	Adjusted HR (95% CI)	P value
Association of change in NLR between baseline and 30 d per 1‐unit increase and outcomes between 30 d and 3 y
Death or rehospitalization	1.17 (1.12–1.22)	<0.0001
All‐cause death	1.17 (1.11–1.23)	<0.0001
Cardiovascular death	1.21 (1.13–1.29)	<0.0001
Rehospitalization	1.16 (1.08–1.24)	<0.0001
Association of change in NLR between baseline and 1 y per 1‐unit decrease and outcomes between 1 y and 3 y
Death or rehospitalization	0.80 (0.76–0.85)	<0.0001
All‐cause death	0.79 (0.73–0.85)	<0.0001
Cardiovascular death	0.77 (0.70–0.85)	<0.0001
Rehospitalization	0.83 (0.77–0.91)	<0.0001

Multivariable models were adjusted for: baseline neutrophil‐to‐lymphocyte ratio (NLR), age, sex, diabetes, body mass index, chronic obstructive pulmonary disease, renal insufficiency (serum creatinine ≥2 mg/dL), previous or current cancer, baseline hemoglobin, serum albumin, previous stroke or transient ischemic attack, atrial fibrillation/flutter, left ventricular ejection fraction, left ventricular end‐diastolic diameter, left ventricular mass, moderate to severe mitral regurgitation, coronary artery disease, peripheral artery disease, New York Heart Association class III or IV, Society of Thoracic Surgeons risk score, access (transfemoral versus transthoracic), randomized treatment, and study cohort. HR indicates hazard ratio; and NLR, neutrophil‐to‐lymphocyte ratio.

Change in NLR in the Overall Population and Clinical Outcomes

When compared with baseline, mean NLR decreased significantly in the overall cohort at both 1 year (0.92, 95% CI, 0.90–0.99; P<0.0001) and 2 years (0.87; 95% CI, 0.84–0.90; P<0.0001). In landmark analysis including adjustment for baseline NLR values, a 1‐unit decrease in NLR between baseline and 1 year was associated with lower risk of death or rehospitalization between 1 year and 3 years (aHR, 0.80; 95% CI, 0.76–0.85; P<0.0001) (Table 3).

Associations Between Change in NLR and Post‐AVR Echocardiographic Indices

Increase in NLR between baseline and 30 days and baseline and 1 year was independently associated with increased risk of moderate or severe paravalvular leak at 30 days and 1 year (Table S9), and a decrease in LVEF at 1 year (Table S10). There was no significant association between change in NLR at follow‐up and mean aortic gradient (Table S11).

Associations Between Change in NLR and Post‐AVR Quality of Life and Functional Outcomes

Increase in NLR between baseline and 30 days and baseline and 1 year was independently associated with worse NYHA class and lower Kansas City Cardiomyopathy Questionnaire and 6‐minute walk test at follow‐up (Table S12 through S14).

Discussion

There were 5 major findings of the present large‐scale analysis of serial NLR in the PARTNER I and II trials and registries of patients with severe AS undergoing TAVR or SAVR: (1) Elevated baseline NLR was independently associated with higher subsequent death and rehospitalization rates regardless of treatment modality; (2) NLR increased more immediately following SAVR compared with TAVR but at 30 days, 1 year, and 2 years NLR decreased to similar levels between TAVR and SAVR; (3) an increase in NLR between baseline and 30 days was associated with increased risk of adverse clinical outcomes and worsened quality of life and functional capacity; (4) from baseline to 1 year, NLR decreased significantly in the overall cohort; and (5) in adjusted landmark analysis, a 1‐unit decrease in NLR from baseline to 1 year was associated with a 15% lower risk of death and 12% lower risk of rehospitalization between 1 year and 3 years.

To the best of our knowledge, the current study is the largest study to date examining the prognostic impact of elevated baseline NLR on clinical outcomes of patients with severe symptomatic AS who undergo AVR. It is also the largest study to compare the change in NLR after TAVR versus SAVR, and to assess the association of this change in NLR with clinical, echocardiographic, and functional outcomes. Only 4 prior studies have investigated the relationship between NLR and clinical outcomes of patients with AS (Table S15) and found a significant association between baseline NLR and increased risk of subsequent events. However, these prior studies , , , included small sample sizes (N=119, 234, 298, and 520), reported single‐center experiences, lacked longitudinal measurements, and did not adjust for important baseline differences between patients with high versus low NLR. In addition, since there is no universal cutoff for NLR that determines a health outcome as “normal” or “adverse,” these prior studies used their own study population to inform arbitrary cutoffs. In the present study, a strong continuous risk relationship was observed between NLR and clinical outcomes.

These findings suggest that NLR may have a role in risk stratification of patients who are more likely to benefit from AVR based on a particular immunologic profile or inflammatory response, which is not currently part of the decision‐making process because of a lack of an easily obtainable or validated biomarker. Changes in NLR over time could serve as a useful tool to identify patients who are at increased risk of worse outcomes following AVR, which may imply a more aggressive follow‐up strategy in these patients.

Several risk factors and conditions associated with increased mortality were more likely present in patients with elevated NLR. It remains to be studied whether elevated NLR has an etiological role in the increased risk of adverse events after AVR or if it is merely a by‐product of the conditions that lead to increased mortality. Several findings of the present analysis suggest that NLR at least reflects the presence of systemic inflammation. First, adjustment for patient characteristics, comorbidities, NYHA class, and Society of Thoracic Surgeons risk score did not alter the association of NLR with subsequent events. Second, although the cohorts included in the pooled analysis differed in surgical risk, the association of NLR with subsequent events remained significant when studying each cohort separately. Third, the inclusion of longitudinal NLR measurements allowed us to assess the natural history and changes over time in NLR. It was interesting to observe that in the present study, mechanical unloading of the heart by AVR was associated with reduced NLR over time. Although controversies exist, a few prior studies of patients with HF have observed a similar association between improvement in cardiac function after cardiac synchronization therapy and a reduction in some inflammatory mediators. However, AVR may not completely reverse the manifestations and pathophysiology of HF, yielding substantial residual risk related to ongoing HF. Emerging data suggest a potential benefit of renin‐angiotensin system inhibition after TAVR on left ventricular remodeling, , and this hypothesis is being tested in the ongoing RASTAVI (Renin‐Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation) trial. Whether aggressive medical therapy such as renin‐angiotensin system inhibition after AVR would benefit those with residual HF and the extent to which improvements in HF symptoms would be accompanied by reduced systemic inflammation in these patients should be studied. Furthermore, reducing procedural complications such as moderate/severe paravalvular leak that is associated with more residual HF might also have an impact on systemic inflammation.

It is also likely that there are other drivers of the association between elevated NLR and worse prognosis after AVR for patients with severe AS than HF or frailty, since adjusting for B‐type natriuretic peptide, NYHA class, and gait speed (as a measure of frailty) did not attenuate the observed association between NLR and the risk of subsequent events. It remains to be studied whether drugs that reduce systemic inflammation might have a role as adjunctive therapy after AVR. Furthermore, it is possible that NLR is a marker of successful pre‐AVR treatment of comorbidities, which would reduce baseline NLR and impact post‐AVR outcomes. Additionally, improvements of AVR technique to decrease the inflammatory response might result in better long‐term outcomes. The early postprocedure increase in NLR, which was greater after SAVR than TAVR, is likely associated with surgical injury and cardiopulmonary bypass. However, this temporary inflammatory period normalized to similar levels as post‐TAVR already at 30 days and NLR decreased similarly in TAVR and SAVR patients. Finally, there was no interaction between NLR and treatment modality (TAVR or SAVR) with regard to the risk of adverse outcomes, suggesting that NLR levels did not influence the choice of treatment.

Limitations

The present study is a post hoc analysis and should be considered hypothesis generating. The patients chosen for this study met the inclusion criteria for the PARTNER trial and therefore were at least intermediate surgical risk. Therefore, the patients in this analysis were elderly with numerous medical comorbidities and may be not representative of the general population of patients who are considered for TAVR or SAVR. Local laboratories were used for NLR measurement, which may have resulted in some imprecision. Although our findings regarding the association of NLR with clinical and functional outcomes remained statistically significant after multivariable adjustment, we cannot rule out the possibility that the analysis is confounded by other unmeasured factors that are correlated with NLR. Additionally, survival bias could have influenced our analyses such as why we did not observe an association between NLR and paravalvular leak at 2 years. Furthermore, data on CRP was not available to compare the prognostic value of NLR in relation to CRP.

Conclusions

In the present study, elevated baseline NLR was associated with worse clinical outcomes in patients with severe AS undergoing TAVR or SAVR. The decrease in NLR after AVR was associated with lower risk of subsequent events in both SAVR and TAVR.

Sources of Funding

The PARTNER trial was funded by Edwards Lifesciences, California.

Disclosures

Dr Lindman serves on the scientific advisory board for Roche Diagnostics, has received research grants from Edwards Lifesciences and Roche Diagnostics, and has consulted for Medtronic. Dr Nazif is a consultant for Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Thourani does research and is a consultant for Abbott Vascular, Allergen, Boston Scientific, Cryolife, Edwards Lifesciences, Gore Vascular, and Jenavalve. Dr Kodali reports institutional research grants from Edwards Lifesciences, Medtronic, and Abbott; consulting fees from Abbott, Admedus, and Meril Lifesciences; and equity options from Biotrace Medical and Thubrikar Aortic Valve Inc. Dr Babaliaros reports institutional research funding from Abbott, Edwards Lifesciences, and Medtronic, consulting fees from Edwards Lifesciences, and equity in Transmural Systems. Dr Herrmann reports institutional research funding from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic; and consulting fees from Abbott, Edwards Lifesciences, and Medtronic. Dr Cohen currently receives research grant support and consulting income from Edwards LifeSciences, Medtronic, Abbott, and Boston Scientific. Dr Mack reports institutional research support (no direct physician compensation) from Edwards Lifesciences. Dr Leon reports institutional research support from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott; and consulting/advisory board participation for Medtronic, Boston Scientific, Gore, Meril Lifescience, and Abbott. Dr George is a consultant for Edwards Lifesciences. Dr Shahim had Region Stockholm’s Clinical Postdoc grant.

Tables S1–S15

Figures S1–S4

Click here for additional data file.