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Neutrophil-lymphocyte ratio as a prognostic marker of outcome in infrapopliteal percutaneous interventions for critical limb ischemia
Neutrophil-lymphocyte ratio as a prognostic marker of outcome in infrapopliteal percutaneous interventions for critical limb ischemia Chun Chan, BRadMedImag, BMBS,a Phillip Puckridge, FRACS,a Shahid Ullah, MS, PhD,b Chris Delaney, BMBS,a and J. Ian Spark, MBChB, FRCS, MD, FRCS(Gen), FRACS,a Adelaide, South Australia, Australia Background: Endovascular intervention has become a frequently used treatment of critical limb ischemia (CLI) in recent times. The recent Bypass vs Angioplasty in Severe Ischaemia of the Leg (BASIL) trial consensus recommended endovascular treatment as a first-line treatment in patients who have a life expectancy that was limited to <2 years. Despite these recommendations, there still remains limited data available to clinicians when seeking to risk stratify patients who present with CLI. The neutrophil-lymphocyte ratio (NLR) has been suggested to be a marker for predicting mortality and patency. This study aimed to investigate the use of the NLR as a prognostic marker for primary patency and mortality after an infrapopliteal endovascular intervention in patients with CLI. Methods: All patients who underwent tibial angioplasty for CLI were retrospectively analyzed. Demographics, degrees of stenosis, vessel patency rates, mortality, and comorbidities were recorded. NLRs were calculated from preoperative blood samples. Primary end points were all-cause mortality, primary patency, and amputation-free survival (AFS) within the follow-up period of 12 months. Multivariate Cox proportional hazard models were used to identify independent predictors. Overall survival, AFS, and the probability of a vessel remaining patent were evaluated by standard Kaplan-Meier survival curves and groups compared by the log-rank test. Results: Eighty-three patients were monitored for 12 months. Ninety limbs were identified, with 104 procedural events and 127 vessels undergoing successful angioplasty. The technical success rate was 86%, and patency at 1 year was 19%. Survival at 1 year was 76% and AFS was 61%. Patients with a NLR $5.25 had an increased risk of death (hazard ratio, 1.97; 95% confidence interval, 1.08-3.62; P [ .03) compared with those with a NLR of <5.25. Furthermore, those with lymphocytes counts of <1.5 3 109/L had higher mortality (hazard ratio, 1.88; 95% confidence interval, 1.02-3.70; P [ .045) than those with lymphocyte counts >1.5 3 109/L. Conclusions: The NLR and absolute lymphocyte counts are potentially valuable prognostic indicators for risk stratification of patient’s presenting with CLI undergoing infrapopliteal angioplasty. (J Vasc Surg 2014;-:1-8.)
Critical limb ischemia (CLI) is associated with significant morbidity and mortality. If left untreated, the natural history of CLI is a 25% to 45% chance of major amputation1 and a 25% chance of death #1 year.2,3 The Bypass vs Angioplasty in Severe Ischaemia of the Leg (BASIL) trial,4 although not specifically looking at tibial interventions, suggested that endovascular intervention should be considered the primary treatment if life expectancy were limited to <2 years. Endovascular intervention is becoming a common approach for CLI associated with infrapopliteal disease, with the primary goal of limb salvage rather than long-term patency.5 Endovascular intervention is From the Department of Vascular Surgery, Flinders Medical Centre and Flinders Universitya; and the Flinders Centre for Epidemiology and Biostatistics, School of Medicine, Faculty of Health Sciences, Flinders University.b Author conflict of interest: none. Reprint requests: J. Ian Spark, MBChB, FRCS, MD, FRCS(Gen), Flinders Medical Centre, Vascular Surgery Department, Flinders Dr, Bedford Park, SA 5042, Australia (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright Ó 2014 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2014.03.277
considered to be cheaper and safer than bypass, with lower associated morbidity, mortality, and hospital stays while achieving limb salvage rates comparable to bypass without precluding later distal bypass surgery.6-11 Restenosis after treatment is a major limitation of tibial endovascular therapy. Restenosis rates are high, with reported rates between 30% and 80%12 at 1 year, but clinical success rates are often higher, with tissue healing persisting despite reocclusion,5 depending on the length of the segment involved and the degree of stenosis. Predicting outcomes after an endovascular intervention for CLI has proven difficult. An association of diabetes mellitus, gangrene, and the presence and degree of renal dysfunction with poor outcomes has been suggested.7,13 The neutrophil-lymphocyte ratio (NLR) is another such potential prognostic marker identified as a useful tool in recognizing patients with potential for adverse outcomes when treated for CLI. Spark et al14 showed the NLR independently predicted death in chronic CLI. The NLR is thought to be a marker of systemic inflammatory burden, which, if elevated, may lead to more aggressive neointimal hyperplasia and restenosis.14 However, the NLR has not been validated as a predictive marker for outcomes in tibial angioplasty for CLI. The aim of this study was to determine whether NLRs are a valid prognostic indicator for restenosis, limb salvage, 1
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or death in patients undergoing an endovascular intervention of the infrapopliteal vessel that present as CLI. METHODS Ethics approval for this study and the study design was obtained from the Institutional Review Board. Study design. The case notes of consecutive patients treated by the Department of Vascular Surgery in a tertiary teaching hospital in South Australia were retrospectively reviewed. All patients who underwent infrapopliteal angioplasty for the treatment of CLI between August 2001 and January 2010 were identified from the Department of Vascular Surgery prospectively collected patient information system. Patients who had infrapopliteal stents were excluded from the study. Patient and laboratory data. Preprocedural and postprocedural angioplasty images were reviewed, and stenoses were graded using the TransAtlantic Inter-Society Consensus (TASC) for the Management of Peripheral Arterial Disease (TASC II) classification.2 The severity of disease was stratified according to the Rutherford classification.15 Blood samples were taken routinely at preadmission clinics for elective interventional cases and at the time of admission for emergency cases. Demographic characteristics, laboratory studies, including leukocyte counts, absolute neutrophil count, and absolute lymphocyte counts, were collected from the hospital patient information system. The NLRs were calculated from the laboratory data (absolute neutrophil count/absolute lymphocyte count). Patients were then stratified by their NLR as <5.25 or $5.25 according to previous published reports on the prognostic value of the NLR.14 Interventions and medical therapy. Infrapopliteal interventions were performed using an anterograde or retrograde approach at the discretion of the treating physician. Heparin was routinely administered during all procedures. After the procedure, routine practice was for patients to be loaded with 300 mg of clopidogrel and to be discharged on a 4-week course of combination antiplatelet therapy consisting of aspirin (100 mg) and clopidogrel (75 mg). Adjuvant medical therapies were prescribed with the end points targeted according to the recommendations from the TASC II guidelines.2 These included the use of b-blockers, antiglycemic therapies, antihypertensives, diuretics, and cholesterol-lowering medications, as indicated on a patientto-patient basis. Nonsteroidal anti-inflammatories were not routinely prescribed and were often contraindicated in light of renal dysfunction in our population; however, whether they were prescribed in between follow-up visits was not recorded. Furthermore, additional wound care clinics and follow-up was arranged for patients with persistent ulcers, as indicated. Surveillance protocol. After the interventions, patients were admitted to the wards for observation and discharged when deemed medically fit by the treating surgeon. Patients were routinely followed up at 3-month intervals in outpatient clinics, at which stage arterial duplex scans were performed to assess vessel patency. The
degree of stenosis was assessed by measuring the peak systolic velocity (PSV) and calculating the peak velocity ratio (intrastenotic PSV divided by the proximally recorded PSV). A peak velocity ratio of >2.4 was reported as a stenosis of >50% according to Ranke et al.16 These patients then underwent angiography at the discretion of the operating surgeon if findings correlated clinically. Complications. Major complications were defined as access site complication requiring surgery, bleeding complications with a drop in hemoglobin levels of $2 g/dL, macroembolization requiring further revascularization or immediate amputation postprocedure. Minor complications were defined as perioperatively complications that did not require further recanalization, including superficial hematoma, minor embolization, and local dissection. Study end points. Primary outcomes were technical success, all-cause mortality, 12-month primary patency, and amputation-free survival (AFS). Technical success was defined as a successful recanalization with <50% residual narrowing and restoration of antegrade perfusion as measured on ultrasound imaging. Primary patency was defined as uninterrupted patency with no procedure at the treated site or on a segment adjacent to it. Statistical analysis. A two-sided log-rank test with an overall sample size of 83 patients achieved 80% power at a 0.05 significance level to detect a minimum hazard ratio (HR) of 1.8 when the NLR was $5.25 and a HR of 1.00 for a NLR of <5.25. Statistical analyses were performed using STATA 12.0 software (StataCorp LP, College Station, Tex) and R 2.15.1 software (The R Foundation for Statistical Computing, http://www. r-project.org/foundation/). Descriptive statistics for interval scale measurements are expressed as mean and standard deviation, and percentages were calculated for categoric data. The outcomes of interest were mortality and primary patency of vessels attempted. Time to event (survival time) was calculated in days from the date of the procedure (baseline) to the survival date, which was date of death, loss to follow-up, or end of follow-up at 12 months. KaplanMeier survival curves were used to estimate survival rates, likelihood of limb salvage, and the probability of vessel patency. Log-rank tests for trend of survival function across categories of covariates were performed. Multivariate Cox proportional hazards regression analysis was applied to calculate the HR for categories of covariates. The models were adjusted by age, gender, Rutherford classification at presentation, TASC score, prescribing rates, year of intervention, and patient comorbidities, which included ischemic heart disease, chronic renal insufficiency, diabetes mellitus type 2, dyslipidemia, and hypertension. Proportional hazard assumptions for the data set were also tested and confirmed to satisfy assumptions. RESULTS We identified 83 patients with ischemia affecting 90 limbs. Patient demographics were typical of patients with severe peripheral arterial disease (Table I). Most patients
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Table I. Demographic and clinical characteristics of 83 patients with 104 admissions NLR Overall
<5.25
$5.25
50 (64.9) 81.0 (76.0-86.0)
25 (55.6) 81.0 (75.0-85.0)
25 (78.1) 82.0 (76.5-86.0)
Variablea Demographic characteristics Male Age, years Risk factors (n ¼ 83 patients) Hypertensionc Ischemic heart disease Diabetes mellitusd Chronic renal impairmente Dyslipidemiaf Rutherford classification IV V VI Modified TASC classification A B C D Disease and intervention Anterior tibial Posterior tibial Tibioperoneal trunk Peroneal No. of vessels attempted 1 2 3
42 49 46 12 29
(54.6) (63.6) (59.7) (15.6) (37.7)
26 23 27 9 17
(57.8) (51.1) (60.0) (20.0) (37.8)
16 26 19 3 12
Pb .04 .70
(50.0) (81.3) (59.4) (9.4) (37.5)
.50 <.01 .96 .21 .98
22 (24.8) 74 (76.3) 1 (1.0)
11 (19.0) 46 (79.3) 1 (1.7)
11 (28.2) 28 (71.8) .
.41 .54 .
. 2 (2.3) 16 (19.8) 61 (77.9)
. 2 (3.8) 9 (17.0) 42 (79.3)
. . 7 (26.9) 19 (73.1)
. . .46 .74
41 21 31 25
30 11 18 12
11 10 13 13
(28.2) (25.6) (33.3) (33.3)
.02 .43 .81 .16
25 (64.1) 13 (33.3) 1 (2.6)
.99 .70 .
(42.3) (21.7) (32.0) (25.8)
62 (63.9) 29 (29.9) 6 (6.2)
(51.7) (19.0) (31.0) (20.7)
37 (63.8) 16 (27.6) 5 (8.6)
NLR, Neutrophil-lymphocyte ratio; TASC, TransAtlantic Inter-Society Consensus. a Categoric data are presented as number (%) and continuous data as median (interquartile range). b P values are based on c2 test for categories and Mann-Whitney U test for age. P values are not available for missing cells: 83 patients for demographic characteristics and risk factors, 104 admissions for Rutherford classification, modified TASC classification, disease and intervention, and number of vessels attempted. c Defined as serial blood pressure measurements >140/90 mm Hg. d Defined as fasting blood glucose test result at or >7.0 mmol/L or a random blood test result at or >11.1 mmol/L. e Defined as serum creatinine >1.5 mg/dL for >3 months. f Defined as history of increased low-density lipoprotein or triglycerides, or low high-density lipoprotein or use of lipid-lowering agents, or both.
had ischemic ulceration or minor gangrene. Of 104 procedures, 71 (68%) angioplasty procedures were performed for isolated infrapopliteal disease, and the remainder (32%) involved concurrent angioplasty of the superfical femoral artery, the popliteal artery, or both. Eight patients underwent multiple angioplasties, including four with bilateral disease and 14 with angioplasty on the ipsilateral side. The tibial vessels that were targeted ranged from a TASC score of B to D, with 16 unable to be assessed due to unavailability of imaging. The most common vessel to undergo angioplasty was the anterior tibial artery, followed by the tibioperoneal trunk and the peroneal artery, with the posterior tibial least involved. The overall initial technical success rate for the study was 85%, with 127 of 149 successfully treated lesions. Survival at 1 year postangioplasty was 76% (Fig 1). AFS was 68% (Fig 2). Patency rates were 55% at 3 months, 44% at 6 months, 28% at 9 months, and 19% at 1 year (Fig 3). Of the 13 failed angioplasty procedures, three limbs (23%) underwent bypass, and two (15%) required amputation. In contrast, for the 77 limbs with successful procedures, 14
(18%) had repeat angioplasty, four (5%) had bypass, and five (6%) had amputations. There were no major procedural complications. Of the 23 minor complications, nonocclusive dissections occurred in nine target vessels (7%), and one patient required superfical femoral artery stenting. Distal embolism occurred in six patients (5%), who were treated with suction embolectomy and glyceryl trinitrate. A postprocedural hematoma developed in five patients (4%), and all were treated conservatively. An arteriovenous fistula formed at the treated segment in two patients (2%), without any clinical consequence. One anterior tibial artery (1%) was perforated. None of the minor complications were associated with any significant clinical consequences and did not require any further revascularization. Patients with a NLR of $5.25 had a 12-month mortality risk that was nearly double that of those with a NLR of <5.25 (1-year mortality of 39% vs 17%; respectively; HR, 1.97; 95% confidence interval [CI], 1.08-3.62; P ¼ .03; Fig 4). Similarly, those with lymphocytes counts of <1.5 109/L also had close to double the chance of
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Fig 1. Kaplan-Meier life table shows overall survival in the 12 months after infrapopliteal endovascular intervention with angioplasty for critical limb ischemia (CLI). The standard error for the calculated Kaplan-Meier curves remained <10% at the 12-month follow-up.
Fig 2. Amputation-free survival (AFS) is shown for the 12 months after infrapopliteal angioplasty for critical limb ischemia (CLI). The standard error for the calculated Kaplan-Meier curves (gray area) remained <10% at the 12month follow-up.
death compared with those with lymphocyte counts >1.5 109/L (36% vs 14%, respectively; HR, 1.88; 95% CI, 1.02-3.70; P ¼ .045; Fig 5). A high NLR was associated with a higher risk of the patient having ischemic heart disease (P < .01) and disease involving the anterior tibial artery (P ¼ .02; Table I). No statistical significance was demonstrated when stratified by absolute neutrophil count (HR, 1.19; 95% CI, 0.63-2.25; P ¼ .61). Furthermore, primary patency at 1 year for the cohort showed no significant difference when stratified by NLR (HR, 1.03; 95% CI, 0.74-1.43; P ¼ .87), lymphocyte (HR, 1.02; 95% CI, 0.73-1.43; P ¼ .91), and neutrophil counts (HR, 0.86; 95% CI, 0.58-1.28; P ¼ .47; Table II). The standard error for calculated Kaplan-Meier curves remained <10% at the 12-month follow-up for overall survival, AFS, and patency. However, the standard error for the survival curves was 14.4% in the group with a lymphocyte count of 1.5 to 3.5 109/L. Analysis with a multivariate model looking at patient demographics and comorbidities identified no significant
association (Table I). However, during the 8 years, there was a significant difference in the severity of the Rutherford classification at presentation, with the latter 5 years showing an increased incidence for patients presenting with more severe symptoms of CLI being offered angioplasty over open procedures. Despite this increase in CLI severity, mortality rates did not differ significantly. Prescribing practice of drug classes was consistent, with no significant differences identified over the time period; however, there was some variability in some of the preferred specific agents within the classes (ie, simvastatin vs atorvastatin, etc). DISCUSSION Clinical decision making and planning for revascularization is difficult in patients presenting with CLI because of severe multiorgan comorbid disease associated with its presentation. Therefore, the identification and implementation of prognostic indicators is greatly beneficial to the clinician. Being able to identify patients who are at high
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Fig 3. Overall patency is shown after infrapopliteal angioplasty for critical limb ischemia (CLI). Patency of vessels was adjudged by ultrasound imaging follow-up at 3 months. The standard error for calculated Kaplan-Meier curves (gray area) remained <10% at the 12-month follow-up.
Fig 4. Survival stratified by a neutrophil-lymphocyte ratio (NLR) of <5.25 (dotted line) and $5.25 (solid line) in patients after infrapopliteal angioplasty for critical limb ischemia (CLI) shows significance between a NLR $5.25 and an increased risk of death. The standard error for calculated Kaplan-Meier curves (gray area) remained <10% at the 12month follow-up. CI, Confidence interval; HR, hazard ratio.
risk of death allows the clinician to use less invasive treatments, such as endovascular intervention, for initial limb salvage. This study found a significant relationship between a high NLR and increased mortality at 1 year for patients with CLI undergoing tibial angioplasty. In the setting of coronary artery disease especially, the NLR has emerged as a powerful predictor of outcome. A high NLR has been shown to be predictive not only for bare-metal stent restenosis17 and progression of atherosclerosis in the coronary arteries18 but, more significantly, also for death after percutaneous coronary intervention and coronary artery bypass grafting.19 Our study suggests that NLR may also correlate with the presence of ischemic heart disease in patients who present with CLI. In the context of peripheral vascular disease, Bhutta et al20 retrospectively analyzed 1021 patients who underwent major vascular surgery (open or endovascular aortic aneurysm repair, lower limb revascularization, or carotid endarterectomy) and found that a preoperative NLR of
>5 identified patients at increased risk of death #2 years. Furthermore, Kullar et al21 found that the postoperative NLR was an independent predictor of graft failure in 126 patients. Spark et al14 have been the only group to investigate the value of the NLR in CLI that included endovascular intervention. In their prospective study of 149 patients presenting with CLI, they found that a preprocedural NLR $5.25 was associated with higher mortality. Our findings correlate with this and suggest that the NLR could also be applied to infrapopliteal vessel angioplasty, with similar correlations in regards to adverse outcomes. In addition, our study has been the first to show that lymphopenia is related to higher risks of death but not primary patency after intervention. In cardiac disease, a low lymphocyte count has been shown to be an independent prognostic marker in heart failure,22 with a suggestion that patients with lower lymphocyte counts tend to be older and have higher rates of comorbid disease,23
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Fig 5. Survival stratified by absolute lymphocyte count of <1.5 109/L (dotted line) and 1.5 to 3.5 109/L (solid line) in patients after infrapopliteal angioplasty for critical limb ischemia (CLI) shows lymphocytosis is a predictor for death. The standard error for the calculated Kaplan-Meier curves (gray area) of patients with lymphocytes at 1.5 to 3.5 109/L was 14.4% at 12 months. CI, Confidence interval; HR, hazard ratio.
Table II. Cox proportional hazard model for survival status and patencya Variable Survival NLR <5.25 $5.25 Lymphocytes, 109/L <1.5 1.5-3.5 Neutrophils, 109/L 1.8-7.5 >7.5 Patency NLR <5.25 $5.25 Lymphocytes, 109/L <1.5 1.5-3.5 Neutrophils, 109/L 1.8-7.5 >7.5 AFS NLR <5.25 $5.25 Lymphocytes, 109/L <1.5 1.5-3.5 Neutrophils, 109/L 1.8-7.5 >7.5
HR
95% CI
P
1 1.97
. 1.08-3.62
. .03
1 0.53
. 0.27-0.98
. .045
1 1.19
. 0.63-2.25
. .61
1 1.03
. 0.74-1.43
. .87
1 1.02
. 0.73-1.43
. .91
1 0.86
. 0.58-1.28
. .47
1 1.86
. 0.83-4.14
. .13
1 0.54
. 0.24-1.25
. .15
1 1.37
. 0.55-3.39
. .5
AFS, Amputation free survival; CI, confidence interval; HR, hazard ratio; NLR, neutrophil-lymphocyte ratio. a The models were adjusted by patients’ demographics (age and gender) and clinical characteristics (hypertension, ischemic heart disease, diabetes mellitus, creatinine, Rutherford classification, and number of vessels attempted).
including diabetes mellitus, renal insufficiency, and atrial fibrillation.19,20 This burden of comorbid disease is also prevalent in our population of patients, with diabetes present in nearly 50% and periprocedural renal dysfunction in just over 60%. Furthermore, these factors have been
previously identified as being associated with poor outcome after vascular intervention6,12 and thus may be reflected in a higher risk of death. We believe that tibial disease may reflect a more aggressive disease process (ie, with greater oxidative free radicals, greater circulating proinflammatory cytokines, etc), with the relative lymphopenia a result of a greater cortisol-induced stress response, and although outside of the scope of this study, it would also be interesting to see whether this lymphopenia translates to an increased risk of other infections, respiratory or otherwise, in this group of patients. No relationship was found between the absolute neutrophil count and primary patency or mortality. This contrasts with a number of studies that have demonstrated that neutrophils are a strong marker to predict adverse cardiovascular outcomes. Toor et al24 retrospectively studied 101 patients who underwent percutaneous transluminal angioplasty and found that preprocedural neutrophils could be used as a global risk factor for adverse outcomes after the procedure. Neutrophils mediate the inflammatory response after vascular injury and have been shown to accumulate at the sites of angioplasty #1 hour postprocedure.25 In animal models, this accumulation of neutrophils has been reported to promote intimal hyperplasia,26 with the localized inflammation resulting in subsequent thrombus formation, intimal hyperplasia development, and potential restenosis.25 Joviliano et al25 suggested that the value of the NLR is that it reflects the neutrophilia of inflammation and the relative lymphopenia of cortisol-induced stress. The results of our study do not dispute this but may suggest that lymphopenia may have a larger role in predicting adverse outcomes than first thought. Our study achieved an AFS rate of 68% at 1 year, which is comparable to current standards reported to be between 75% and 100%.5,27 Similarly, our 1-year survival rate was 76%, which is also comparable to the 65% to 78% reported in the literature. Nair et al5 suggested that clinical success is often higher than long-term primary patency rates because healing of wounds can occur in 3 to 6 months and persist
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despite vessel reocclusion, which may be demonstrated by good AFS despite relatively poor primary patency. If NLR is correlated with poorer outcomes, how should clinicians approach patients with ratios $5.25? Unfortunately, there is currently no evidence in the literature to guide how to directly affect this measure. NLR is a reflection of the systemic inflammatory burden created by the systemic disease state of atherosclerosis. We know that pharmacotherapy, such as with aspirin and statins, which are recommended for the treatment of atherosclerotic risk factors, also have pleiotropic anti-inflammatory properties that have seen their use proposed as an adjuvant treatment for patients with sepsis.28 In atherosclerosis in particular, high-dose statin therapy has been demonstrated to exert anti-inflammatory effects, modulate endothelial function, and inhibit the thrombotic signaling cascade and has the potential to lead to plaque/disease regression.29,30 As an extension of this idea, one could speculate that maximizing secondary prevention with pharmacotherapy may also be likely to reduce NLR. However, further work is required to define and confirm this concept, which unfortunately falls outside the scope of this study. Further limitations of this study were its retrospective design, and further prospective trials are required to further elucidate the value of the NLR in the setting of peripheral vascular disease. Furthermore, due the limited sample size, there may be type II statistical error when not having found correlations among NLR, lymphocytes, and neutrophils with patency. Despite these limitations, NLR represents an attractive test for clinicians as a risk assessment model, especially given the simplicity and ready availability of the neutrophil and lymphocyte counts as a preoperative workup. We recommend that an NLR be calculated for all patients presenting with CLI. Those who are undergoing endovascular procedures and have a high preprocedural NLR or lymphopenia are at higher risk and may warrant aggressive preoperative optimization of risk factors and more diligent follow-up. CONCLUSIONS The preprocedural NLR may represent a valuable prognostic marker of increased risk of death after infrapopliteal angioplasty for CLI. Our retrospective study demonstrated an independent correlation between an increased NLR and lymphopenia with a greater risk of death. This study suggests that NLR and lymphocyte counts may be valid tools to risk stratify patients being considered for tibial angioplasty. However, further prospective trials are required to elucidate the validity of this measurement. AUTHOR CONTRIBUTIONS Conception and design: CC, PP Analysis and interpretation: CC, PP, SU, CD, IS Data collection: CC Writing the article: CC, PP, SU, CD, IS
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Critical revision of the article: CC, PP, SU, CD, IS Final approval of the article: CC, PP, SU, CD, IS Statistical analysis: CC, SU Obtained funding: Not applicable Overall responsibility: IS REFERENCES 1. Benoit E, O’Donnell TF Jr, Kitsios GD, Iafrati MD. Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement. J Vasc Surg 2012;55:781-9. 2. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33(Suppl 1):S1-75. 3. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463-654. 4. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, et al. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: multicentre, randomised controlled trial. Lancet 2005;366: 1925-34. 5. Nair V, Chaisson G, Abben R. Strategies in infrapopliteal intervention: improving outcomes in challenging patients. J Interv Cardiol 2009;22: 27-36. 6. Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira A, De Luccia N. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg 2008;47:975-81. 7. Peregrin JH, Koznar B, Kovác J, Lastovicková J, Novotný J, Vedlich D, et al. PTA of infrapopliteal arteries: long-term clinical follow-up and analysis of factors influencing clinical outcome. Cardiovasc Intervent Radiol 2010;33:720-5. 8. Conrad MF, Kang J, Cambria RP, Brewster DC, Watkins MT, Kwolek CJ, et al. Infrapopliteal balloon angioplasty for the treatment of chronic occlusive disease. J Vasc Surg 2009;50:799-805.e4. 9. Giles KA, Pomposelli FB, Spence TL, Hamdan AD, Blattman SB, Panossian H, et al. Infrapopliteal angioplasty for critical limb ischemia: relation of TransAtlantic InterSociety Consensus class to outcome in 176 limbs. J Vasc Surg 2008;48:128-36. 10. Söderström MI, Arvela EM, Korhonen M, Halmesmäki KH, Albäck AN, Biancari F, et al. Infrapopliteal percutaneous transluminal angioplasty versus bypass surgery as first-line strategies in critical leg ischemia: a propensity score analysis. Ann Surg 2010;252:765-73. 11. Casella IB, Brochaso-Neto FC, Sandri Gde A, Kalaf MJ, Godoy MR, Costa VS, et al. Outcome analysis of infrapopliteal percutaneous transluminal angioplasty and bypass graft surgery with nonreversed saphenous vein for individuals with critical limb ischemia. Vasc Endovascular Surg 2010;44:625-32. 12. Schwarzwalder U, Zeller T. Below-the-knee revascularization. Advanced techniques. J Cardiovasc Surg (Torino) 2009;50:627-34. 13. Venermo M, Biancari F, Arvela E, Korhonen M, Söderström M, Halmesmäki K, et al. The role of chronic kidney disease as a predictor of outcome after revascularisation of the ulcerated diabetic foot. Diabetologia 2011;54:2971-7. 14. Spark JI, Sarveswaran J, Blest N, Charalabidis P, Asthana S. An elevated neutrophil-lymphocyte ratio independently predicts mortality in chronic critical limb ischemia. J Vasc Surg 2010;52:632-6.
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15. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997;26:517. 16. Ranke C, Rieder M, Creutzig A, Alexander K. [A nomogram of duplex ultrasound quantification of peripheral arterial stenoses. Studies of the cardiovascular model and in angiography patients]. Med Klin (Munich) 1995;90:72-7. German. 17. Turak O, Ozcan F, Isleyen A, Tok D, Sokmen E, Buyukkaya E, et al. Usefulness of the neutrophil-to-lymphocyte ratio to predict bare-metal stent restenosis. Am J Cardiol 2012;110:1405-10. 18. Kalay N, Dogdu O, Koc F, Yarlioglues M, Ardic I, Akpek M, et al. Hematologic parameters and angiographic progression of coronary atherosclerosis. Angiology 2012;63:213-7. 19. Tasoglu I, Turak O, Nazli Y, Ozcan F, Colak N, Sahin S, et al. Preoperative neutrophil-lymphocyte ratio and saphenous vein graft patency after coronary artery bypass grafting [published online ahead of print April 10, 2013]. Clin Appl Thromb Hemost http://dx.doi. org/10.1177/1076029613484086. 20. Bhutta H, Agha R, Wong J, Tang TY, Wilson YG, Walsh SR. Neutrophil-lymphocyte ratio predicts medium-term survival following elective major vascular surgery: a cross-sectional study. Vasc Endovasc Surg 2011;45:227-31. 21. Kullar P, Weerakoddy R, Walsh S. Neutrophil-lymphocyte ratio predicts graft patency following lower limb revascularisation. Acta Chir Belg 2012;112:365-8. 22. Rudiger A, Burckhardt OA, Harpes P, Müller SA, Follath F. The relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failure. Am J Emerg Med 2006;24:451-4.
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23. Vaduganathan M, Ambrosy AP, Greene SJ, Mentz RJ, Subacius HP, Maggioni AP, et al. Predictive value of low relative lymphocyte count in patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial. Circ Heart Fail 2012;5: 750-8. 24. Toor IS, Jaumdally RJ, Moss MS, Babu SB. Preprocedural neutrophil count predicts outcome in patients with advanced peripheral vascular disease undergoing percutaneous transluminal angioplasty. J Vasc Surg 2008;48:1504-8. 25. Joviliano EE, Piccinato CE, Dellalibera-Joviliano R, Moriya T, Évora PR. Inflammatory markers and restenosis in peripheral percutaneous angioplasty with intravascular stenting: current concepts. Ann Vasc Surg 2011;25:846-55. 26. Shimazawa M, Watanabe S, Kondo K, Hara H, Nakashima M, Umemura K. Neutrophil accumulation promotes intimal hyperplasia after photochemically induced arterial injury in mice. Eur J Pharmacol 2005;520:156-63. 27. Rana MA, Gloviczk P. Endovascular interventions for infrapopliteal arterial disease: an update. Semin Vasc Surg 2012;25:29-34. 28. Sanchez MA, Thomas CB, O’Neal HR. Do aspirin and statins prevent severe sepsis? Curr Opin Infect Dis 2012;25:345-50. 29. Guarini G, Marzilli M. Defining the role of high-dose statins in PCI. Am J Cardiovasc Drugs 2013;13:189-97. 30. Puri R, Nissen SE, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, et al. Factors underlying regression of coronary atheroma with potent statin therapy. Eur Heart J 2013;34:1818-25.
Submitted Dec 23, 2013; accepted Mar 25, 2014.
Critical limb ischemia (CLI) is associated with significant morbidity and mortality. If left untreated, the natural history of CLI is a 25% to 45% chance of major amputation1 and a 25% chance of death #1 year.2,3 The Bypass vs Angioplasty in Severe Ischaemia of the Leg (BASIL) trial,4 although not specifically looking at tibial interventions, suggested that endovascular intervention should be considered the primary treatment if life expectancy were limited to <2 years. Endovascular intervention is becoming a common approach for CLI associated with infrapopliteal disease, with the primary goal of limb salvage rather than long-term patency.5 Endovascular intervention is From the Department of Vascular Surgery, Flinders Medical Centre and Flinders Universitya; and the Flinders Centre for Epidemiology and Biostatistics, School of Medicine, Faculty of Health Sciences, Flinders University.b Author conflict of interest: none. Reprint requests: J. Ian Spark, MBChB, FRCS, MD, FRCS(Gen), Flinders Medical Centre, Vascular Surgery Department, Flinders Dr, Bedford Park, SA 5042, Australia (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright Ó 2014 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2014.03.277
considered to be cheaper and safer than bypass, with lower associated morbidity, mortality, and hospital stays while achieving limb salvage rates comparable to bypass without precluding later distal bypass surgery.6-11 Restenosis after treatment is a major limitation of tibial endovascular therapy. Restenosis rates are high, with reported rates between 30% and 80%12 at 1 year, but clinical success rates are often higher, with tissue healing persisting despite reocclusion,5 depending on the length of the segment involved and the degree of stenosis. Predicting outcomes after an endovascular intervention for CLI has proven difficult. An association of diabetes mellitus, gangrene, and the presence and degree of renal dysfunction with poor outcomes has been suggested.7,13 The neutrophil-lymphocyte ratio (NLR) is another such potential prognostic marker identified as a useful tool in recognizing patients with potential for adverse outcomes when treated for CLI. Spark et al14 showed the NLR independently predicted death in chronic CLI. The NLR is thought to be a marker of systemic inflammatory burden, which, if elevated, may lead to more aggressive neointimal hyperplasia and restenosis.14 However, the NLR has not been validated as a predictive marker for outcomes in tibial angioplasty for CLI. The aim of this study was to determine whether NLRs are a valid prognostic indicator for restenosis, limb salvage, 1
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or death in patients undergoing an endovascular intervention of the infrapopliteal vessel that present as CLI. METHODS Ethics approval for this study and the study design was obtained from the Institutional Review Board. Study design. The case notes of consecutive patients treated by the Department of Vascular Surgery in a tertiary teaching hospital in South Australia were retrospectively reviewed. All patients who underwent infrapopliteal angioplasty for the treatment of CLI between August 2001 and January 2010 were identified from the Department of Vascular Surgery prospectively collected patient information system. Patients who had infrapopliteal stents were excluded from the study. Patient and laboratory data. Preprocedural and postprocedural angioplasty images were reviewed, and stenoses were graded using the TransAtlantic Inter-Society Consensus (TASC) for the Management of Peripheral Arterial Disease (TASC II) classification.2 The severity of disease was stratified according to the Rutherford classification.15 Blood samples were taken routinely at preadmission clinics for elective interventional cases and at the time of admission for emergency cases. Demographic characteristics, laboratory studies, including leukocyte counts, absolute neutrophil count, and absolute lymphocyte counts, were collected from the hospital patient information system. The NLRs were calculated from the laboratory data (absolute neutrophil count/absolute lymphocyte count). Patients were then stratified by their NLR as <5.25 or $5.25 according to previous published reports on the prognostic value of the NLR.14 Interventions and medical therapy. Infrapopliteal interventions were performed using an anterograde or retrograde approach at the discretion of the treating physician. Heparin was routinely administered during all procedures. After the procedure, routine practice was for patients to be loaded with 300 mg of clopidogrel and to be discharged on a 4-week course of combination antiplatelet therapy consisting of aspirin (100 mg) and clopidogrel (75 mg). Adjuvant medical therapies were prescribed with the end points targeted according to the recommendations from the TASC II guidelines.2 These included the use of b-blockers, antiglycemic therapies, antihypertensives, diuretics, and cholesterol-lowering medications, as indicated on a patientto-patient basis. Nonsteroidal anti-inflammatories were not routinely prescribed and were often contraindicated in light of renal dysfunction in our population; however, whether they were prescribed in between follow-up visits was not recorded. Furthermore, additional wound care clinics and follow-up was arranged for patients with persistent ulcers, as indicated. Surveillance protocol. After the interventions, patients were admitted to the wards for observation and discharged when deemed medically fit by the treating surgeon. Patients were routinely followed up at 3-month intervals in outpatient clinics, at which stage arterial duplex scans were performed to assess vessel patency. The
degree of stenosis was assessed by measuring the peak systolic velocity (PSV) and calculating the peak velocity ratio (intrastenotic PSV divided by the proximally recorded PSV). A peak velocity ratio of >2.4 was reported as a stenosis of >50% according to Ranke et al.16 These patients then underwent angiography at the discretion of the operating surgeon if findings correlated clinically. Complications. Major complications were defined as access site complication requiring surgery, bleeding complications with a drop in hemoglobin levels of $2 g/dL, macroembolization requiring further revascularization or immediate amputation postprocedure. Minor complications were defined as perioperatively complications that did not require further recanalization, including superficial hematoma, minor embolization, and local dissection. Study end points. Primary outcomes were technical success, all-cause mortality, 12-month primary patency, and amputation-free survival (AFS). Technical success was defined as a successful recanalization with <50% residual narrowing and restoration of antegrade perfusion as measured on ultrasound imaging. Primary patency was defined as uninterrupted patency with no procedure at the treated site or on a segment adjacent to it. Statistical analysis. A two-sided log-rank test with an overall sample size of 83 patients achieved 80% power at a 0.05 significance level to detect a minimum hazard ratio (HR) of 1.8 when the NLR was $5.25 and a HR of 1.00 for a NLR of <5.25. Statistical analyses were performed using STATA 12.0 software (StataCorp LP, College Station, Tex) and R 2.15.1 software (The R Foundation for Statistical Computing, http://www. r-project.org/foundation/). Descriptive statistics for interval scale measurements are expressed as mean and standard deviation, and percentages were calculated for categoric data. The outcomes of interest were mortality and primary patency of vessels attempted. Time to event (survival time) was calculated in days from the date of the procedure (baseline) to the survival date, which was date of death, loss to follow-up, or end of follow-up at 12 months. KaplanMeier survival curves were used to estimate survival rates, likelihood of limb salvage, and the probability of vessel patency. Log-rank tests for trend of survival function across categories of covariates were performed. Multivariate Cox proportional hazards regression analysis was applied to calculate the HR for categories of covariates. The models were adjusted by age, gender, Rutherford classification at presentation, TASC score, prescribing rates, year of intervention, and patient comorbidities, which included ischemic heart disease, chronic renal insufficiency, diabetes mellitus type 2, dyslipidemia, and hypertension. Proportional hazard assumptions for the data set were also tested and confirmed to satisfy assumptions. RESULTS We identified 83 patients with ischemia affecting 90 limbs. Patient demographics were typical of patients with severe peripheral arterial disease (Table I). Most patients
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Chan et al 3
Table I. Demographic and clinical characteristics of 83 patients with 104 admissions NLR Overall
<5.25
$5.25
50 (64.9) 81.0 (76.0-86.0)
25 (55.6) 81.0 (75.0-85.0)
25 (78.1) 82.0 (76.5-86.0)
Variablea Demographic characteristics Male Age, years Risk factors (n ¼ 83 patients) Hypertensionc Ischemic heart disease Diabetes mellitusd Chronic renal impairmente Dyslipidemiaf Rutherford classification IV V VI Modified TASC classification A B C D Disease and intervention Anterior tibial Posterior tibial Tibioperoneal trunk Peroneal No. of vessels attempted 1 2 3
42 49 46 12 29
(54.6) (63.6) (59.7) (15.6) (37.7)
26 23 27 9 17
(57.8) (51.1) (60.0) (20.0) (37.8)
16 26 19 3 12
Pb .04 .70
(50.0) (81.3) (59.4) (9.4) (37.5)
.50 <.01 .96 .21 .98
22 (24.8) 74 (76.3) 1 (1.0)
11 (19.0) 46 (79.3) 1 (1.7)
11 (28.2) 28 (71.8) .
.41 .54 .
. 2 (2.3) 16 (19.8) 61 (77.9)
. 2 (3.8) 9 (17.0) 42 (79.3)
. . 7 (26.9) 19 (73.1)
. . .46 .74
41 21 31 25
30 11 18 12
11 10 13 13
(28.2) (25.6) (33.3) (33.3)
.02 .43 .81 .16
25 (64.1) 13 (33.3) 1 (2.6)
.99 .70 .
(42.3) (21.7) (32.0) (25.8)
62 (63.9) 29 (29.9) 6 (6.2)
(51.7) (19.0) (31.0) (20.7)
37 (63.8) 16 (27.6) 5 (8.6)
NLR, Neutrophil-lymphocyte ratio; TASC, TransAtlantic Inter-Society Consensus. a Categoric data are presented as number (%) and continuous data as median (interquartile range). b P values are based on c2 test for categories and Mann-Whitney U test for age. P values are not available for missing cells: 83 patients for demographic characteristics and risk factors, 104 admissions for Rutherford classification, modified TASC classification, disease and intervention, and number of vessels attempted. c Defined as serial blood pressure measurements >140/90 mm Hg. d Defined as fasting blood glucose test result at or >7.0 mmol/L or a random blood test result at or >11.1 mmol/L. e Defined as serum creatinine >1.5 mg/dL for >3 months. f Defined as history of increased low-density lipoprotein or triglycerides, or low high-density lipoprotein or use of lipid-lowering agents, or both.
had ischemic ulceration or minor gangrene. Of 104 procedures, 71 (68%) angioplasty procedures were performed for isolated infrapopliteal disease, and the remainder (32%) involved concurrent angioplasty of the superfical femoral artery, the popliteal artery, or both. Eight patients underwent multiple angioplasties, including four with bilateral disease and 14 with angioplasty on the ipsilateral side. The tibial vessels that were targeted ranged from a TASC score of B to D, with 16 unable to be assessed due to unavailability of imaging. The most common vessel to undergo angioplasty was the anterior tibial artery, followed by the tibioperoneal trunk and the peroneal artery, with the posterior tibial least involved. The overall initial technical success rate for the study was 85%, with 127 of 149 successfully treated lesions. Survival at 1 year postangioplasty was 76% (Fig 1). AFS was 68% (Fig 2). Patency rates were 55% at 3 months, 44% at 6 months, 28% at 9 months, and 19% at 1 year (Fig 3). Of the 13 failed angioplasty procedures, three limbs (23%) underwent bypass, and two (15%) required amputation. In contrast, for the 77 limbs with successful procedures, 14
(18%) had repeat angioplasty, four (5%) had bypass, and five (6%) had amputations. There were no major procedural complications. Of the 23 minor complications, nonocclusive dissections occurred in nine target vessels (7%), and one patient required superfical femoral artery stenting. Distal embolism occurred in six patients (5%), who were treated with suction embolectomy and glyceryl trinitrate. A postprocedural hematoma developed in five patients (4%), and all were treated conservatively. An arteriovenous fistula formed at the treated segment in two patients (2%), without any clinical consequence. One anterior tibial artery (1%) was perforated. None of the minor complications were associated with any significant clinical consequences and did not require any further revascularization. Patients with a NLR of $5.25 had a 12-month mortality risk that was nearly double that of those with a NLR of <5.25 (1-year mortality of 39% vs 17%; respectively; HR, 1.97; 95% confidence interval [CI], 1.08-3.62; P ¼ .03; Fig 4). Similarly, those with lymphocytes counts of <1.5 109/L also had close to double the chance of
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Fig 1. Kaplan-Meier life table shows overall survival in the 12 months after infrapopliteal endovascular intervention with angioplasty for critical limb ischemia (CLI). The standard error for the calculated Kaplan-Meier curves remained <10% at the 12-month follow-up.
Fig 2. Amputation-free survival (AFS) is shown for the 12 months after infrapopliteal angioplasty for critical limb ischemia (CLI). The standard error for the calculated Kaplan-Meier curves (gray area) remained <10% at the 12month follow-up.
death compared with those with lymphocyte counts >1.5 109/L (36% vs 14%, respectively; HR, 1.88; 95% CI, 1.02-3.70; P ¼ .045; Fig 5). A high NLR was associated with a higher risk of the patient having ischemic heart disease (P < .01) and disease involving the anterior tibial artery (P ¼ .02; Table I). No statistical significance was demonstrated when stratified by absolute neutrophil count (HR, 1.19; 95% CI, 0.63-2.25; P ¼ .61). Furthermore, primary patency at 1 year for the cohort showed no significant difference when stratified by NLR (HR, 1.03; 95% CI, 0.74-1.43; P ¼ .87), lymphocyte (HR, 1.02; 95% CI, 0.73-1.43; P ¼ .91), and neutrophil counts (HR, 0.86; 95% CI, 0.58-1.28; P ¼ .47; Table II). The standard error for calculated Kaplan-Meier curves remained <10% at the 12-month follow-up for overall survival, AFS, and patency. However, the standard error for the survival curves was 14.4% in the group with a lymphocyte count of 1.5 to 3.5 109/L. Analysis with a multivariate model looking at patient demographics and comorbidities identified no significant
association (Table I). However, during the 8 years, there was a significant difference in the severity of the Rutherford classification at presentation, with the latter 5 years showing an increased incidence for patients presenting with more severe symptoms of CLI being offered angioplasty over open procedures. Despite this increase in CLI severity, mortality rates did not differ significantly. Prescribing practice of drug classes was consistent, with no significant differences identified over the time period; however, there was some variability in some of the preferred specific agents within the classes (ie, simvastatin vs atorvastatin, etc). DISCUSSION Clinical decision making and planning for revascularization is difficult in patients presenting with CLI because of severe multiorgan comorbid disease associated with its presentation. Therefore, the identification and implementation of prognostic indicators is greatly beneficial to the clinician. Being able to identify patients who are at high
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Fig 3. Overall patency is shown after infrapopliteal angioplasty for critical limb ischemia (CLI). Patency of vessels was adjudged by ultrasound imaging follow-up at 3 months. The standard error for calculated Kaplan-Meier curves (gray area) remained <10% at the 12-month follow-up.
Fig 4. Survival stratified by a neutrophil-lymphocyte ratio (NLR) of <5.25 (dotted line) and $5.25 (solid line) in patients after infrapopliteal angioplasty for critical limb ischemia (CLI) shows significance between a NLR $5.25 and an increased risk of death. The standard error for calculated Kaplan-Meier curves (gray area) remained <10% at the 12month follow-up. CI, Confidence interval; HR, hazard ratio.
risk of death allows the clinician to use less invasive treatments, such as endovascular intervention, for initial limb salvage. This study found a significant relationship between a high NLR and increased mortality at 1 year for patients with CLI undergoing tibial angioplasty. In the setting of coronary artery disease especially, the NLR has emerged as a powerful predictor of outcome. A high NLR has been shown to be predictive not only for bare-metal stent restenosis17 and progression of atherosclerosis in the coronary arteries18 but, more significantly, also for death after percutaneous coronary intervention and coronary artery bypass grafting.19 Our study suggests that NLR may also correlate with the presence of ischemic heart disease in patients who present with CLI. In the context of peripheral vascular disease, Bhutta et al20 retrospectively analyzed 1021 patients who underwent major vascular surgery (open or endovascular aortic aneurysm repair, lower limb revascularization, or carotid endarterectomy) and found that a preoperative NLR of
>5 identified patients at increased risk of death #2 years. Furthermore, Kullar et al21 found that the postoperative NLR was an independent predictor of graft failure in 126 patients. Spark et al14 have been the only group to investigate the value of the NLR in CLI that included endovascular intervention. In their prospective study of 149 patients presenting with CLI, they found that a preprocedural NLR $5.25 was associated with higher mortality. Our findings correlate with this and suggest that the NLR could also be applied to infrapopliteal vessel angioplasty, with similar correlations in regards to adverse outcomes. In addition, our study has been the first to show that lymphopenia is related to higher risks of death but not primary patency after intervention. In cardiac disease, a low lymphocyte count has been shown to be an independent prognostic marker in heart failure,22 with a suggestion that patients with lower lymphocyte counts tend to be older and have higher rates of comorbid disease,23
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Fig 5. Survival stratified by absolute lymphocyte count of <1.5 109/L (dotted line) and 1.5 to 3.5 109/L (solid line) in patients after infrapopliteal angioplasty for critical limb ischemia (CLI) shows lymphocytosis is a predictor for death. The standard error for the calculated Kaplan-Meier curves (gray area) of patients with lymphocytes at 1.5 to 3.5 109/L was 14.4% at 12 months. CI, Confidence interval; HR, hazard ratio.
Table II. Cox proportional hazard model for survival status and patencya Variable Survival NLR <5.25 $5.25 Lymphocytes, 109/L <1.5 1.5-3.5 Neutrophils, 109/L 1.8-7.5 >7.5 Patency NLR <5.25 $5.25 Lymphocytes, 109/L <1.5 1.5-3.5 Neutrophils, 109/L 1.8-7.5 >7.5 AFS NLR <5.25 $5.25 Lymphocytes, 109/L <1.5 1.5-3.5 Neutrophils, 109/L 1.8-7.5 >7.5
HR
95% CI
P
1 1.97
. 1.08-3.62
. .03
1 0.53
. 0.27-0.98
. .045
1 1.19
. 0.63-2.25
. .61
1 1.03
. 0.74-1.43
. .87
1 1.02
. 0.73-1.43
. .91
1 0.86
. 0.58-1.28
. .47
1 1.86
. 0.83-4.14
. .13
1 0.54
. 0.24-1.25
. .15
1 1.37
. 0.55-3.39
. .5
AFS, Amputation free survival; CI, confidence interval; HR, hazard ratio; NLR, neutrophil-lymphocyte ratio. a The models were adjusted by patients’ demographics (age and gender) and clinical characteristics (hypertension, ischemic heart disease, diabetes mellitus, creatinine, Rutherford classification, and number of vessels attempted).
including diabetes mellitus, renal insufficiency, and atrial fibrillation.19,20 This burden of comorbid disease is also prevalent in our population of patients, with diabetes present in nearly 50% and periprocedural renal dysfunction in just over 60%. Furthermore, these factors have been
previously identified as being associated with poor outcome after vascular intervention6,12 and thus may be reflected in a higher risk of death. We believe that tibial disease may reflect a more aggressive disease process (ie, with greater oxidative free radicals, greater circulating proinflammatory cytokines, etc), with the relative lymphopenia a result of a greater cortisol-induced stress response, and although outside of the scope of this study, it would also be interesting to see whether this lymphopenia translates to an increased risk of other infections, respiratory or otherwise, in this group of patients. No relationship was found between the absolute neutrophil count and primary patency or mortality. This contrasts with a number of studies that have demonstrated that neutrophils are a strong marker to predict adverse cardiovascular outcomes. Toor et al24 retrospectively studied 101 patients who underwent percutaneous transluminal angioplasty and found that preprocedural neutrophils could be used as a global risk factor for adverse outcomes after the procedure. Neutrophils mediate the inflammatory response after vascular injury and have been shown to accumulate at the sites of angioplasty #1 hour postprocedure.25 In animal models, this accumulation of neutrophils has been reported to promote intimal hyperplasia,26 with the localized inflammation resulting in subsequent thrombus formation, intimal hyperplasia development, and potential restenosis.25 Joviliano et al25 suggested that the value of the NLR is that it reflects the neutrophilia of inflammation and the relative lymphopenia of cortisol-induced stress. The results of our study do not dispute this but may suggest that lymphopenia may have a larger role in predicting adverse outcomes than first thought. Our study achieved an AFS rate of 68% at 1 year, which is comparable to current standards reported to be between 75% and 100%.5,27 Similarly, our 1-year survival rate was 76%, which is also comparable to the 65% to 78% reported in the literature. Nair et al5 suggested that clinical success is often higher than long-term primary patency rates because healing of wounds can occur in 3 to 6 months and persist
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despite vessel reocclusion, which may be demonstrated by good AFS despite relatively poor primary patency. If NLR is correlated with poorer outcomes, how should clinicians approach patients with ratios $5.25? Unfortunately, there is currently no evidence in the literature to guide how to directly affect this measure. NLR is a reflection of the systemic inflammatory burden created by the systemic disease state of atherosclerosis. We know that pharmacotherapy, such as with aspirin and statins, which are recommended for the treatment of atherosclerotic risk factors, also have pleiotropic anti-inflammatory properties that have seen their use proposed as an adjuvant treatment for patients with sepsis.28 In atherosclerosis in particular, high-dose statin therapy has been demonstrated to exert anti-inflammatory effects, modulate endothelial function, and inhibit the thrombotic signaling cascade and has the potential to lead to plaque/disease regression.29,30 As an extension of this idea, one could speculate that maximizing secondary prevention with pharmacotherapy may also be likely to reduce NLR. However, further work is required to define and confirm this concept, which unfortunately falls outside the scope of this study. Further limitations of this study were its retrospective design, and further prospective trials are required to further elucidate the value of the NLR in the setting of peripheral vascular disease. Furthermore, due the limited sample size, there may be type II statistical error when not having found correlations among NLR, lymphocytes, and neutrophils with patency. Despite these limitations, NLR represents an attractive test for clinicians as a risk assessment model, especially given the simplicity and ready availability of the neutrophil and lymphocyte counts as a preoperative workup. We recommend that an NLR be calculated for all patients presenting with CLI. Those who are undergoing endovascular procedures and have a high preprocedural NLR or lymphopenia are at higher risk and may warrant aggressive preoperative optimization of risk factors and more diligent follow-up. CONCLUSIONS The preprocedural NLR may represent a valuable prognostic marker of increased risk of death after infrapopliteal angioplasty for CLI. Our retrospective study demonstrated an independent correlation between an increased NLR and lymphopenia with a greater risk of death. This study suggests that NLR and lymphocyte counts may be valid tools to risk stratify patients being considered for tibial angioplasty. However, further prospective trials are required to elucidate the validity of this measurement. AUTHOR CONTRIBUTIONS Conception and design: CC, PP Analysis and interpretation: CC, PP, SU, CD, IS Data collection: CC Writing the article: CC, PP, SU, CD, IS
Chan et al 7
Critical revision of the article: CC, PP, SU, CD, IS Final approval of the article: CC, PP, SU, CD, IS Statistical analysis: CC, SU Obtained funding: Not applicable Overall responsibility: IS REFERENCES 1. Benoit E, O’Donnell TF Jr, Kitsios GD, Iafrati MD. Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement. J Vasc Surg 2012;55:781-9. 2. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33(Suppl 1):S1-75. 3. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463-654. 4. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, et al. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: multicentre, randomised controlled trial. Lancet 2005;366: 1925-34. 5. Nair V, Chaisson G, Abben R. Strategies in infrapopliteal intervention: improving outcomes in challenging patients. J Interv Cardiol 2009;22: 27-36. 6. Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira A, De Luccia N. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg 2008;47:975-81. 7. Peregrin JH, Koznar B, Kovác J, Lastovicková J, Novotný J, Vedlich D, et al. PTA of infrapopliteal arteries: long-term clinical follow-up and analysis of factors influencing clinical outcome. Cardiovasc Intervent Radiol 2010;33:720-5. 8. Conrad MF, Kang J, Cambria RP, Brewster DC, Watkins MT, Kwolek CJ, et al. Infrapopliteal balloon angioplasty for the treatment of chronic occlusive disease. J Vasc Surg 2009;50:799-805.e4. 9. Giles KA, Pomposelli FB, Spence TL, Hamdan AD, Blattman SB, Panossian H, et al. Infrapopliteal angioplasty for critical limb ischemia: relation of TransAtlantic InterSociety Consensus class to outcome in 176 limbs. J Vasc Surg 2008;48:128-36. 10. Söderström MI, Arvela EM, Korhonen M, Halmesmäki KH, Albäck AN, Biancari F, et al. Infrapopliteal percutaneous transluminal angioplasty versus bypass surgery as first-line strategies in critical leg ischemia: a propensity score analysis. Ann Surg 2010;252:765-73. 11. Casella IB, Brochaso-Neto FC, Sandri Gde A, Kalaf MJ, Godoy MR, Costa VS, et al. Outcome analysis of infrapopliteal percutaneous transluminal angioplasty and bypass graft surgery with nonreversed saphenous vein for individuals with critical limb ischemia. Vasc Endovascular Surg 2010;44:625-32. 12. Schwarzwalder U, Zeller T. Below-the-knee revascularization. Advanced techniques. J Cardiovasc Surg (Torino) 2009;50:627-34. 13. Venermo M, Biancari F, Arvela E, Korhonen M, Söderström M, Halmesmäki K, et al. The role of chronic kidney disease as a predictor of outcome after revascularisation of the ulcerated diabetic foot. Diabetologia 2011;54:2971-7. 14. Spark JI, Sarveswaran J, Blest N, Charalabidis P, Asthana S. An elevated neutrophil-lymphocyte ratio independently predicts mortality in chronic critical limb ischemia. J Vasc Surg 2010;52:632-6.
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Submitted Dec 23, 2013; accepted Mar 25, 2014.