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Clinical Chemistry 55: 68-77, 2009. First published November 6, 2008; 10.1373/clinchem.2008.108753
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(Clinical Chemistry. 2009;55:68-77.)
© 2009 American Association for Clinical Chemistry, Inc.

Proteomics and Protein Markers

Amino-Terminal Pro–B-Type Natriuretic Peptide as Predictor of Mortality in Patients with Symptomatic Peripheral Arterial Disease: 5-Year Follow-Up Data from the Linz Peripheral Arterial Disease Study

Thomas Mueller1,a, Benjamin Dieplinger1, Werner Poelz2, Georg Endler3, Oswald F. Wagner3 and Meinhard Haltmayer1,4

1 Department of Laboratory Medicine, Konventhospital Barmherzige Brueder Linz, Linz, Austria; 2 Institute for Applied System Sciences and Statistics, University of Linz, Linz, Austria; 3 Department of Medical and Clinical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria; 4 Paracelsus Private Medical University, Salzburg, Austria.

aAddress correspondence to this author at: Department of Laboratory Medicine, Koventhospital Barmherzige Brueder, Seilerstaette 2-4, A-4020 Linz, Austria. Fax +43-732-7677-3799; e-mail thomas.mueller{at}bs-lab.at


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Amino-terminal pro–B-type natriuretic peptide (NT-proBNP) has emerged as predictor of mortality endpoints in cardiac disease. In contrast, the prognostic value of NT-proBNP in patients with peripheral arterial disease (PAD) is unclear. Therefore, we aimed to evaluate the capability of NT-proBNP as a marker for long-term prognosis in atherosclerotic PAD.

Methods: We obtained NT-proBNP serum concentrations in 487 consecutive patients with symptomatic PAD admitted to a tertiary-care hospital. The endpoint was defined as all-cause mortality, and the study participants were followed for 5 years.

Results: Of the 487 patients enrolled, 114 died and 373 survived during follow-up. The median NT-proBNP concentration was higher among decedents than survivors (692 vs 143 ng/L; P < 0.001). Using the median NT-proBNP concentration of the entire cohort (213 ng/L) as threshold level, Kaplan–Meier curve analysis demonstrated that the survival probability was lower in patients with NT-proBNP above the median (log-rank test, P < 0.001). In the fully adjusted Cox proportional-hazards regression analysis, NT-proBNP >213 ng/L had a risk ratio of 2.27 (95% CI 1.27–4.03; P = 0.005) independent of age, sex, glomerular filtration rate, clinical stage of PAD, cardiovascular comorbidity, and other potential confounders. Further analyses showed that NT-proBNP added significantly to the value of established and emerging outcome predictors of PAD.

Conclusions: In this study, a NT-proBNP serum concentration >213 ng/L was a robust and independent predictor of 5-year all-cause mortality in patients with symptomatic PAD. Thus, NT-proBNP measurements can be considered a valuable tool for risk stratification in these patients.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Atherosclerotic peripheral arterial disease (PAD)1 , an important manifestation of systemic atherosclerosis, is characterized by arterial stenoses and occlusions in the peripheral arterial bed of the lower limbs (1)(2). Individuals with PAD have a substantially increased risk of cardiovascular morbidity and mortality than those without PAD (3) and suffer from combined annual rates of heart attack, stroke, and hospitalization that are comparable to or greater than rates observed in established coronary artery disease (CAD) (4)(5). Therefore, risk management in the setting of existing atherosclerotic vascular disease remains a major health challenge (6). However, risk prediction tools have not been established among patients with PAD to identify who is likely destined for adverse outcome.

Current primary risk assessment involves the application of traditional cardiac risk factor analysis often using equations derived from large observational studies (7)(8). Risk stratification in the PAD population may be further influenced by several factors, including underlying comorbid diseases, clinical stage of PAD, and hemodynamic severity of the disease (9). This staging, however, might ignore the importance of other factors, which may also be independent contributors to long-term survival. Thus, improving cardiovascular risk assessment may require another approach, such as looking for biologic markers that reflect components of the pathophysiology of cardiovascular events (10).

The amino-terminal fragment of B-type natriuretic peptide prohormone (NT-proBNP) is a marker for functional cardiac impairment and is increased in heart disease with or without symptoms (11)(12). In patients with cardiac disease, determination of NT-proBNP provides reliable diagnostic and prognostic information (11)(12). Among many other proposed applications for NT-proBNP measurements, the prognostic value of NT-proBNP in patients with PAD might be of particular interest. Given the frequent comorbid conditions in PAD patients as mentioned, the application of NT-proBNP as a prognostic marker could be clinically useful in these patients, because NT-proBNP concentrations increase in proportion to severity of cardiac disease (11)(12) and might have potential as therapeutic targets (6)(13)(14).

In this study, we therefore addressed the value of circulating NT-proBNP as a marker for long-term prognosis in atherosclerotic PAD. We tested the hypothesis that increased NT-proBNP concentrations are independently associated with 5-year all-cause mortality in patients with symptomatic PAD.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study population
To evaluate the capability of NT-proBNP measurements for mortality in patients with symptomatic PAD, we used our data from the Linz Peripheral Arterial Disease (LIPAD) study (15), which was designed to evaluate possible phenotypic and genotypic risk factors for atherosclerotic PAD and to determine the predictive value of potential markers on long-term outcome of PAD patients as a prospectively conducted study. The study protocol was approved by the local ethics committee in accordance with the Declaration of Helsinki, and all study participants gave informed consent. The LIPAD study objectives, recruitment procedures, and characteristics have been described in detail (15). In brief, 487 consecutive patients with symptomatic atherosclerotic PAD admitted to the St. John of God Hospital (Linz, Austria) for inpatient diagnostics and treatment of chronic limb ischemia were enrolled between April 2000 and April 2002. The patients were enrolled upon admission to the hospital (i.e., baseline data were obtained before any specific inpatient treatment or any modification of therapy for this particular hospitalization). Study participants underwent evaluation for the presence of risk factors for atherosclerosis and comorbid conditions at baseline (e.g., arterial hypertension, diabetes, smoking), as recommended (16).

PAD was defined as chronic atherosclerotic disease of the lower extremities associated with typical symptoms, such as claudication or leg pain on exertion, rest pain, or minor or major tissue loss, and was verified by interview; physical examination; Doppler segmental blood pressure measurement of the lower limbs, including continuous wave spectral analysis and resting ankle-brachial index measurements; and intraarterial aortofemoral angiography. PAD patients were included in this study based on the final clinical diagnosis established by the attending vascular surgeons. All cases with acute ischemia (peripheral arterial thrombosis of a native artery, popliteal artery aneurysm, or acutely thrombosed peripheral bypass grafts) were excluded. Additional exclusion criteria were PAD attributable to nonatherosclerotic causes (cardioembolic disease, thromboangiitis obliterans, vasculitis, or congenital or metabolic vascular disease) and a history or presence of any malignancy at the time of enrollment. Clinical stage of PAD was classified as claudication or critical limb ischemia according to Rutherford et al. (16).

CAD was defined as remote myocardial infarction by history, occult myocardial infarction by electrocardiography, or previous coronary bypass surgery or percutaneous transluminal coronary angioplasty. Cerebrovascular disease was defined as history of transient or temporary stroke or completed stroke with permanent neurologic deficit. In this study, cardiovascular comorbidity was defined as having either CAD or cerebrovascular disease or both. Because patients were admitted for inpatient diagnostics and treatment of PAD, none of them suffered acute coronary syndrome, acute stroke, or transient or temporary stroke at the time of enrollment.

Evaluation and diagnosis of symptomatic heart failure (HF) at baseline was left to the discretion of the attending physicians. The diagnosis of symptomatic HF was based on the clinical picture with typical symptoms, signs of enlarged heart and congestion in chest x-ray, and echocardiography when performed. Of note, echocardiography was performed under clinical conditions without standardized requirements, and thus may be considered exploratory only. However, appropriate information on left ventricular ejection fraction (i.e., ≥50% or <50%) was recorded for all echocardiography findings.

biochemical analyses
At baseline evaluation, blood was collected by venipuncture after overnight fasting. Creatinine, glucose, glycohemoglobin A1c, total cholesterol, and triglycerides were analyzed with standard assays using a COBAS Integra analyzer (Roche Diagnostics). HDL and LDL cholesterol was measured by quantitative electrophoresis with enzymatic staining (Helena BioSciences Europe). Total homocysteine, folate, and vitamin B12 assays were performed using an AxSYM analyzer (Abbott Diagnostics). C-reactive protein (CRP) was measured by a high-sensitivity assay (N High Sensitivity CRP) using a BN ProSpec analyzer (Dade Behring). Estimated glomerular filtration rate (eGFR) was calculated as recently recommended (17). Serum samples for NT-proBNP determination were immediately frozen and stored at –80 °C until assessment. NT-proBNP concentrations were measured using an Elecsys 2010 instrument (Roche Diagnostics); the technical properties of this assay and imprecision data for our laboratory have been reported (18).

mortality ascertainment
We obtained mortality data for the entire cohort from the Austrian Death Registry, resulting in date of death and cause of death encoded before 2002 according to the International Classification of Diseases, Ninth Revision (ICD9) or after 2002 according to ICD10. The Austrian Death Registry includes all deaths within Austria and the deaths of Austrian citizens in foreign countries if reported to Austrian officials. According to Austrian laws, all patients must undergo a postmortem examination if the final cause of death is not evident from the patient history, resulting in an overall postmortem frequency of 39% in our study.

The outcome variable of the present follow-up investigation was all-cause mortality, defined as death occurring during the observation period. Cardiovascular mortality was defined as ICD9/ICD10 codes 390–459/I00–I99 and cancer mortality as ICD9/ICD10 codes 140–239/C00–D48. The remaining ICD9/ICD10 codes were summarized as mortality attributable to other causes. All 487 study participants received follow-up, and the assigned observation period for each of them was 5 years (i.e., exactly 1825 days from the time of enrollment) or until time of death, if earlier. For the attending physicians and vascular surgeons, NT-proBNP results were not available during the whole follow-up time.

statistical analysis
We analyzed data using SPSS 13.0 software (SPSS Inc.) and MedCalc 8.0.0.0 package (MedCalc Software). Dichotomous data were given as absolute numbers (percent), and continuous variables were presented as median (25th–75th percentiles) unless otherwise indicated. Univariate comparisons between decedents and survivors were performed using the {chi}2 test for categorical variables and with the nonparametric Mann–Whitney U-test for continuous variables (respective P values were not adjusted for multiple comparisons and are therefore descriptive only). The whole study population was then stratified according to the median NT-proBNP serum concentration. Using this approach, we computed Kaplan–Meier estimates of the distribution of times from baseline to death and performed the log-rank test to compare the survival curves between the 2 groups. Furthermore, we used univariate and multivariate Cox proportional-hazards regression analyses to analyze the effect of several potential confounders on survival. We also used Cox proportional-hazards regression to explore whether NT-proBNP increased the value of established and emerging outcome predictors of PAD. Probabilities were 2-tailed, and P values <0.05 were regarded statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A cohort of 487 patients with symptomatic atherosclerotic PAD (i.e., chronic limb ischemia) were enrolled into the LIPAD study. The study comprised 340 male and 147 female individuals with a median age of 70 years (range 38–94). Classification of the clinical stage of PAD revealed 393 patients with claudication and 94 patients with critical limb ischemia. Of the total cohort, 153 had concomitant CAD and 99 had concomitant cerebrovascular disease, resulting in 212 patients with cardiovascular comorbidity (113 had merely CAD, 59 had merely cerebrovascular disease, and 40 had both). Symptomatic HF was diagnosed in 32 study participants. Echocardiography was performed in 198 patients, and in 57 of them a left ventricular ejection fraction <50% was evident. Furthermore, 113 patients had ≥50% carotid stenosis. Another 20 patients were classified as having stenosis ≥50% as well, because they had undergone previous carotid surgery to treat stenosis. The study sample included 287 patients with first manifestation of symptomatic PAD and 200 patients with remote vascular surgery, percutaneous transluminal angioplasty (PTA) with or without stenting, or amputation.

On admission (the time of patient enrollment), 249 patients were on antiplatelet therapy (229 aspirin and 20 clopidogrel), 55 on oral anticoagulation, and 116 on lipid-lowering drugs. Of the 487 patients enrolled, 172 patients were treated conservatively during this in-hospital stay, and 315 had interventions (1 or more of the following: vascular surgery, PTA with or without stenting, lumbar sympathectomy, amputation). Medicinal therapy was subsequently modified during the in-hospital stay in most patients. Four patients died while in the hospital. At discharge from the hospital, 384 patients received antiplatelet therapy (aspirin and/or clopidogrel), 106 oral anticoagulation (20 of them in combination with antiplatelet therapy), and 227 lipid-lowering medication (215 statins, 10 fibrates, and 2 both). Furthermore, with respect to antihypertensive treatment, 76 patients had a single medication, 98 a 2-fold combination, and 120 a ≥3-fold combination. Overall, 112 patients took β-blockers at the time of discharge, 193 angiotensin-converting enzyme inhibitors, 19 angiotensin II-antagonists, 85 calcium-antagonists, 37 {alpha}1-receptor blockers, 19 {alpha}2-agonists, 48 loop diuretics, 142 thiazide diuretics, and 20 potassium-sparing diuretics.

Each of the 487 PAD patients enrolled received follow-up; 114 died and 373 survived 5 years from the time they were enrolled. Cardiovascular mortality was established in 69 patients, cancer mortality in 14, and mortality attributable to other causes in 31. The baseline patient characteristics for the survivors and decedents are shown in Table 1 . The median NT-proBNP serum concentration was significantly higher among decedents than survivors (692 vs 143 ng/L; P < 0.001). Rates of death at 5 years as a function of NT-proBNP sextiles are depicted in Fig. 1 , displaying a relationship between rising NT-proBNP serum concentrations and increased rates of death, indicating a threshold effect at the median NT-proBNP concentration of the entire cohort. Kaplan–Meier curve analysis of the 487 study participants, stratified into 2 groups according to the median NT-proBNP serum concentration of the entire cohort at baseline (i.e., 213 ng/L), is shown in Fig. 2 . Mortality was significantly higher in patients with baseline NT-proBNP serum concentrations above the median (log-rank test, P < 0.001).


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  		Table 1. Baseline characteristics of patients with symptomatic PAD according to survival.1


Figure 1
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  		Figure 1. Rates of death at 5 years as a function of NT-proBNP serum concentrations in patients with symptomatic PAD.


Figure 2
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  		Figure 2. Kaplan–Meier plot showing survival in 487 patients with symptomatic PAD who were stratified into 2 groups according to the median NT-proBNP serum concentrations of the entire cohort at baseline.

The results of Cox proportional-hazards regression analyses are given in Table 2 . As detailed, in univariate analysis a NT-proBNP serum concentration above the median displayed a risk ratio (RR) of 4.80 (95% CI 3.03–7.58; P < 0.001). In the fully adjusted Cox proportional-hazards regression analysis, NT-proBNP concentrations >213 ng/L had RR 2.27 (95% CI 1.27–4.03; P = 0.005) independent of age, sex, eGFR, clinical stage of PAD, cardiovascular comorbidity, and other factors as specified in Table 2 , model 5. In this statistical model, only age (P < 0.001), clinical stage of PAD (P = 0.001), smoking status (P = 0.020), and the presence of cardiovascular comorbidity (P = 0.042) contributed independently to outcome in addition to NT-proBNP; all other included variables failed to reach statistical significance.


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  		Table 2. Results of Cox proportional-hazards regression analyzing the capability of NT-proBNP for the prediction of 5-year all cause mortality in patients with symptomatic PAD, independent of possible confounding variables.1

To explore whether NT-proBNP added to the value of established and emerging outcome predictors of PAD, we computed the RRs of mortality by Cox proportional-hazards regression analyses in which the study participants were stratified into 4 groups according to median NT-proBNP serum concentrations (low ≤213 ng/L vs high >213 ng/L), median patient age (low <70 years vs high ≥70 years), median eGFR (high ≥74mL/min/1.73 m2 vs low <74mL/min/1.73 m2), clinical stage of PAD (claudication vs critical limb ischemia), presence of cardiovascular comorbidity (not present vs present), median high-sensitivity CRP (low ≤4.2 mg/L vs high >4.2 mg/L), and median total homocystein (low ≤16.3 µmol/L vs high >16.3 µmol/L), respectively. As shown in Fig. 3 , the RRs were consistently the highest among patients with high NT-proBNP concentrations.


Figure 3
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  		Figure 3. RRs of all-cause mortality in symptomatic PAD for NT-proBNP serum concentrations in combination with other established and emerging outcome predictors of PAD.

Study participants were stratified into 4 groups according to median NT-proBNP serum concentrations and median patients’ age (A), median eGFR (B), clinical stage of PAD (claudication vs critical limb ischemia) (C), presence of cardiovascular comorbidity (no cardiovascular comorbidity vs cardiovascular comorbidity) (D), median high-sensitivity CRP (E), and median total homocysteine (F).

As secondary analyses, we evaluated cutoff values for NT-proBNP according to the FDA-cleared package insert of the Roche assay (125 ng/L for those <75 years old and 450 ng/L for those ≥75) and the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study cutoff values stratified by renal function (eGFR ≥60 mL/min/1.73 m2 and age <50 years = 450 ng/L, and age ≥50 years = 900 ng/L; eGFR <60 mL/min/1.73 m2 age-independent = 1200 ng/L) (19). When calculating univariate Cox proportional-hazards regression analyses similar to Table 2Up , model 1, NT-proBNP concentrations above the FDA cutoff values had RR for mortality of 2.64 (95% CI 1.77–3.92; P < 0.001), and NT-proBNP concentrations above the PRIDE cutoff values had RR for mortality of 4.77 (95% CI 3.27–6.96; P < 0.001). In fully adjusted Cox proportional-hazards regression analyses, NT-proBNP concentrations above the FDA cutoff values had RR of 1.58 (95% CI 0.91–2.74; P = 0.102), and NT-proBNP concentrations above the PRIDE cutoff values had RR of 2.40 (95% CI 1.32–4.37; P = 0.004), independent of other confounders in each case analogous to the analysis presented in Table 2Up , model 5.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study provides strong evidence that high circulating NT-proBNP concentrations obtained in patients with atherosclerotic PAD are associated with an increased risk for long-term mortality. In the present study, a NT-proBNP serum concentration >213 ng/L was a robust predictor of 5-year all-cause mortality in PAD patients independent of other confounders. In addition, when the value of circulating NT-proBNP was combined with several established and emerging outcome predictors of PAD for risk stratification, increased NT-proBNP serum concentrations added significantly to the value of each of these predictors. Thus, NT-proBNP measurements can be considered a valuable tool for risk stratification in symptomatic PAD.

As outlined previously, several algorithms incorporating various indices have been proposed in an attempt to assess an individual patient’s prognosis in PAD (9). However, most single indices are characterized by unsatisfactory discrimination of patients with and without increased mortality. As a result of this study, NT-proBNP might fulfill the requirements of a clinically useful marker for prognosis and risk stratification in the setting of symptomatic PAD. Currently, B-type natriuretic peptides (i.e., BNP and NT-proBNP) are increasingly used as diagnostic markers in patients with suspected HF because these peptides can rule out HF with a high negative predictive value (18)(20)(21)(22). In addition, high prognostic value for B-type natriuretic peptides has been a consistent finding among different populations from the community (23)(24), in patients with HF (25)(26)(27), and in patients with CAD (28)(29)(30). The results of our study extend this evidence by demonstrating that NT-proBNP also has prognostic value in patients with established PAD.

B-type natriuretic peptides have been evaluated in several studies on PAD patients to date. Two smaller studies were able to show that circulating NT-proBNP is substantially higher in PAD patients than in controls (31)(32). This might be, at least in part, explained by a higher prevalence of HF in PAD than in an age- and sex-matched control population as demonstrated in a recently published metaanalysis (33). The prevalence of HF in our cohort (approximately 6%–7%) was similar to the prevalence reported in this metaanalysis. Four published studies provide evidence that increased concentrations of B-type natriuretic peptides are associated with an increased risk for adverse peri- and postoperative outcome in PAD patients undergoing noncardiac surgery (34)(35)(36)(37)(38). Furthermore, 1 large study assessed the prognostic role of eGFR and NT-proBNP for mortality endpoints in a vascular population (including PAD patients) (39); however, the authors failed to demonstrate a significant prognostic role of NT-proBNP in their study sample, and the data were only suggestive for PAD patients. Thus, the finding of that study contrasts with the results obtained in our PAD cohort, where NT-proBNP was a strong and independent predictor of 5-year all-cause mortality. Reasons for the conflicting results between the 2 studies may include differences in disease severity (e.g., not explicitly stated but probably nonhospitalized and asymptomatic vs hospitalized and symptomatic in our study), differences in renal function (mean eGFR 56 vs median 74 mL/min/1.73 m2 in our study), and different design of assays used for NT-proBNP determination (Pierce SearchLight vs Roche Diagnostics in our study).

It was not the primary aim of the present study to evaluate indices for adverse outcome in PAD other than NT-proBNP. Nevertheless, it can be derived from our fully adjusted Cox proportional-hazards regression analysis that age, presence of critical limb ischemia and cardiovascular comorbidity, and smoking status contributed independently to the outcome of our patients. This finding is in accordance with the literature (9). However, resting ankle-brachial index—as a marker for hemodynamic severity of the disease—was not independently associated with worse outcome in our cohort. Although an abnormal resting ankle-brachial index clearly identifies a high-risk population among otherwise healthy individuals, it is conceivable that the resting ankle-brachial index value in patients with established PAD may not provide information on the future risk of adverse outcome (9). A possible reason for the apparent lack of prognostic value of the ankle-brachial index in our study is reflected in the relative fractions of patients in our cohort with first manifestation of symptomatic PAD (59%) vs patients in whom vascular interventions (remote vascular surgery, PTA with or without stenting, amputation) had been performed (41%). As the resting ankle-brachial index increases due to adequately performed vascular interventions and/or surgery, it is clear that these procedures modulate the predictive value of the resting ankle-brachial index in the patients concerned, despite sustained high risk for, e.g., cardiovascular morbidity and mortality.

In our primary analyses, we used a single cutoff value for NT-proBNP, namely 213 ng/L, which was the median of the entire cohort. As secondary analyses, we evaluated cutoff values for NT-proBNP according to the FDA-cleared package insert of the Roche assay (stratified by age) and PRIDE (stratified by renal function and age) (19). The FDA cutoff values appeared to have an inferior ability for the prediction of mortality in this study, whereas the cutoff values derived from PRIDE had prognostic capability similar to that of our 213 ng/L cutoff. Both the FDA and PRIDE cutoff values facilitate rather high NT-proBNP concentrations, and probably NT-proBNP indicates an increased risk for mortality at even lower concentrations. Nevertheless, it was shown that NT-pro BNP is a robust predictor of mortality in PAD by demonstrating that risk prediction is possible with the analyte at various cutoff values.

Our study has several potential limitations. One limitation of the single-center study is that our cohort was a selected subgroup of the overall PAD population. Thus, the findings cannot be generalized to asymptomatic PAD patients or patients who do not meet criteria for hospitalization. Another limitation is related to the assessment of HF—probably the true prevalence of HF is higher than stated for our cohort, but as mentioned previously the evaluation and diagnosis of HF was left to the discretion of the attending physicians and was based on clinical criteria only without using an acknowledged HF classification score. In addition, we acknowledge that echocardiography was not carried out in a standardized manner but should be considered rather exploratory, and the rate of patients in whom echocardiography was performed was only 41% in our cohort. Although we believe this rate is relatively high compared with common practice in clinical routine settings, we were not able to adjust multivariable analyses for ejection fraction at baseline. This is a real-life study, however, demonstrating that cardiac evaluation of PAD patients is not always optimal in clinical practice. Therefore, the demonstration that a single NT-proBNP measurement provides reliable predictive information in patients with symptomatic PAD might have clinical implications.

In conclusion, NT-proBNP was a strong and independent predictor of 5-year all-cause mortality in our cohort. This finding is novel and could be an important step in improving treatment of PAD patients in the future because a high proportion of these patients might suffer undiagnosed heart disease. As there is abundant evidence pointing to the fact that HF patients who are evaluated and treated by specialists (i.e., cardiologists) have better outcomes, we propose that circulating NT-proBNP should be measured in (hospitalized) patients with symptomatic PAD, and increased concentrations should initiate further diagnostic actions and therapeutic interventions for reducing circulating NT-proBNP and thereby improving outcome in these patients. However, this concept is currently speculative and further prospective studies will be necessary, randomizing patients with symptomatic PAD to those receiving and those not receiving NT-proBNP determinations and comparing the perceived outcome in the 2 groups.


   Acknowledgments
 
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: None declared.

Stock Ownership: None declared.

Honoraria: T. Mueller has received speaking fees from Roche Diagnostics.

Research Funding: Roche Diagnostics (Vienna, Austria) provided reagents for NT-proBNP measurements free of charge.

Expert Testimony: None declared.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.

Acknowledgments: We thank Peter Bayer (Statistik Austria) for providing data from the Austrian death registry. We further thank Hans Dieplinger and Franz Hinterreiter for helpful discussions and critical reading of the manuscript.


   Footnotes
 
1 Nonstandard abbreviations: PAD, peripheral arterial disease; CAD, coronary artery disease; NT-proBNP, N-terminal pro–B-type natriuretic peptide; LIPAD, Linz Peripheral Arterial Disease; HF, heart failure; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; ICD9, International Classification of Diseases, Ninth Revision; PTA, percutaneous transluminal angioplasty; RR, risk ratio; PRIDE, ProBNP Investigation of Dyspnea in the Emergency Department.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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E. Di Angelantonio, R. Chowdhury, N. Sarwar, K. K. Ray, R. Gobin, D. Saleheen, A. Thompson, V. Gudnason, N. Sattar, and J. Danesh
B-Type Natriuretic Peptides and Cardiovascular Risk: Systematic Review and Meta-Analysis of 40 Prospective Studies
Circulation, December 1, 2009; 120(22): 2177 - 2187.
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