Journal of Vascular Surgery
Volume 50, Issue 2 , Pages 317-321, August 2009

Preprocedural hemoglobin predicts outcome in peripheral vascular disease patients undergoing percutaneous transluminal angioplasty

Department of Radiology, City Hospital, Birmingham, United Kingdom

Received 3 November 2008; accepted 22 March 2009.

Article Outline

Background

Anemia is a risk factor for adverse outcome in patients with symptomatic cardiovascular disease. This study assessed the association of preprocedural hemoglobin with adverse outcome in patients with advanced peripheral vascular disease (PVD) undergoing percutaneous transluminal angioplasty (PTA).

Methods

Consecutive first-time procedures for patients with Rutherford category 4 or 5 PVD who underwent successful nonemergency PTA were analyzed in a retrospective cohort study. Cardiovascular risk factors, preprocedural hemoglobin, and angiographic data were recorded. Preprocedural (≤24 hours) hemoglobin was divided into tertiles (first tertile: 10.5 ± 0.7 g/dL; second tertile: 12.0 ± 0.4 g/dL; third tertile: 13.9 ± 0.9 g/dL). Study end points were a composite of adverse peripheral vascular events consisting of target lesion revascularization (repeat PTA or vascular bypass operation), limb amputation, or death. Cox regression analysis was used to identify independent predictors of adverse peripheral vascular outcome.

Results

A total of 101 patients (mean age, 76 ± 10 years) were studied, of which 54 (53%) were men, and 62 (65%) were anemic. We observed 42 events during a median of 14 months (interquartile range, 4-26 months follow-up). Cox regression analysis found preprocedural hemoglobin in the first tertile vs third tertile (odds ratio, 4.17; 95% confidence interval, 1.56-11.16, P = .004), diabetes, renal failure, Rutherford category 5, and tibial vessels runoff score were independent predictors of adverse peripheral vascular outcome.

Conclusions

Anemia is a common comorbid condition in patients with advanced PVD. Preprocedural hemoglobin could be used in clinical practice to risk stratify patients with advanced PVD who are being considered for PTA. Correction of anemia before PTA in patients with Rutherford category 4 and 5 PVD may improve long-term outcome. Further investigation is needed regarding the optimization of preprocedural hemoglobin.

 

Atherosclerosis impairs tissue perfusion and reduces the delivery of oxygen to metabolically active tissue. Anemia can further affect oxygen delivery, such that chronic anemia in heart failure patients has consistently been associated with a significantly increased risk of death.1, 2, 3 Sarnal et al4 demonstrated that in patients with a history of coronary artery disease (CAD), evidence of anemia was associated with an increased risk of long-term adverse cardiovascular outcome. For those patients undergoing percutaneous coronary intervention for symptomatic CAD, preprocedural anemia increases the risk of both in-hospital and long-term mortality.5, 6, 7 Similarly, anemia in patients undergoing coronary artery bypass grafting is associated with higher in-hospital mortality.8 Given a shared pathophysiology between peripheral vascular disease (PVD) and CAD, anemia is also associated with an increased risk of short-term and long-term mortality in patients undergoing elective open vascular surgery for PVD.9

The adverse effect of anemia on long-term outcome depends on its severity and the presence of comorbidities.9, 10 In the case of mild to moderate anemia, oxygen delivery is maintained through increased tissue oxygen extraction.11 In symptomatic PVD, however, an imbalance exists between oxygen demand and delivery that may be further compromised by even mild anemia. To the best of our knowledge, there are no data in the literature addressing the prognostic effect of mild anemia in PVD patients undergoing percutaneous transluminal angioplasty (PTA). The aim of our study was to determine the effect of preprocedural hemoglobin concentrations on long-term adverse peripheral vascular outcome in patients with advanced PVD undergoing PTA.

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Methods 

This retrospective cohort study included consecutive patients with Rutherford12 category 4 or 5 PVD who underwent successful first-time nonemergency PTA within a large district general hospital between 2002 and 2004. The diagnosis of PVD was assigned by means of clinical evaluation or duplex ultrasound imaging and was confirmed by lower limb angiography. The study excluded patients with a history of surgical lower limb amputation as a consequence of PVD or previous surgical or endovascular lower limb revascularization.

Baseline clinical characteristics were defined by patient self-reporting. Data was collected on age, gender, history of diabetes mellitus, hypertension, smoking, angina, myocardial infarction, stroke, heart failure, and renal impairment (history of elevated creatinine levels). Preprocedural (≤24 hours) hemoglobin concentration in g/dL was divided into first tertile, 10.5 ± 0.7; second tertile, 12.0 ± 0.4, or third tertile, 13.9 ± 0.9. Anemia was defined according to the criteria of the World Health Organization (<12.0 g/dL in women and <13.0 g/dL in men).13

A standardized protocol was used for peripheral angiography and PTA.14 Before PTA, patients received 3000 IU of intravenous heparin. All interventions were performed by experienced interventional radiologists, and the PTA technique used was at the discretion of the treating interventional radiologists. Primary technical success was defined as a residual stenosis of <50% at the dilated segment.14 The most severe lesion treated, as determined by the length and degree of stenosis, was identified as the index lesion for the procedure and had follow-up for repeat intervention.

The arterial distributions reported represent the location of the index lesion. Lesions were categorized as involving the superficial femoral artery, common femoral artery, or popliteal artery, and also according to the TransAtlantic Inter-Society Consensus (TASC) classification of arterial lesions.15 Angiographic documentation of preprocedural tibial runoff vessels was available for all patients. Each of the three tibial vessels were assigned a run-off score according to the extent of luminal disease: 0 (<50% stenosis), 1 (50%-99% stenosis) or 2 (occluded); and the sum of this formed the total runoff score (range, 0-6).16 Patients were stratified into two groups of tibial vessels runoff score: 0 to 2 vs 3 to 6.

During the study period, all patients received life-long aspirin alternatively or clopidogrel if aspirin was contraindicated. Patients were routinely followed up in the outpatient clinic every 6 months for clinical evaluation of symptoms. The study end points included the occurrence of adverse peripheral vascular events, including target lesion revascularization (repeat PTA or vascular bypass operation), surgical limb amputation, or death. After a study end point was reached patients were no longer monitored for the occurrence of further study end points.

Statistical analysis 

Categoric variables are expressed as frequencies and percentages, and differences between groups were assessed using the Pearson χ2 or the two-tailed Fisher exact test. Continuous variables are expressed as mean ± standard deviation, and those with a normal distribution were analyzed using a Student t test. Odds ratios (OR) are reported with a 95% confidence interval (CI). Cox regression analysis was used to identify independent predictors of adverse peripheral vascular outcome. Kaplan-Meier survival analysis was used to compare differences in event rates between tertiles of preprocedural hemoglobin levels using the log-rank test. Statistical analysis was completed using SPSS 14.0 software (SPSS Inc, Chicago, Ill). For analyses, a value of P ≤ .05 was considered statistically significant.

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Results 

We studied 101 consecutive patients (53% men) who were admitted with advanced PVD undergoing nonemergency PTA. Of these, 32 were in Rutherford category 4 and 69 were at category 5. The mean patient age was 76 ± 10 years, 54% were diabetic, 68% were hypertensive, and 27% were smokers (Table I). Balloon angioplasty was to the superficial femoral artery in 12 patients, common femoral artery in 16, popliteal artery in 26, or tibial artery in 47. Preprocedural femoral-popliteal lesions were classified according to TASC criteria and included type A in 33, type B in 35, type C in 22, and type D in 11. The preprocedural tibial vessels runoff scores were 0 in 10 patients, 1 in 15, 2 in 16, 3 in 11, 4 in 29, 5 in 9, and 6 in 11. The grouped tibial vessels runoff scores were 0 to 2 in 41 patients and 3 to 6 in 60. Of the total study population, 62 patients (65%) were anemic.

Table I. Baseline clinical characteristics according to clinical outcome
VariablesaOverallNo eventAdverse eventP
Patients, No.1015942
Age, y76 ± 1077 ± 1075 ± 11.41
Male gender54(53)25(42)29(69).01
Diabetes55(54)25(42)30(71).01
Hypertension69(68)40(68)29(69)>.99
Smoker27(27)14(24)13(31).50
Angina27(27)13(22)14(33).26
Myocardial infarction12(12)2(3)10(24).003
Stroke15(15)10(17)5(12).58
Heart failure17(17)5(8)12(29).01
Renal impairment15(15)4(7)11(26).01
Serum creatinine, mmol/L111 ± 8297 ± 37129 ± 116.04
Rutherford category 569(68)35(59)34(81).03
Angiographic data
Tibial run-off score >260(59)26(44)34(81)<.001

aCategoric variables are expressed as number (%); continuous variables are expressed as mean ± standard deviation.

There were no in-hospital events. During the median follow-up of 14 months (interquartile range, 4-26 months), 42 adverse peripheral vascular events occurred, with 11 repeat PTAs, 9 vascular bypass operations, 9 below or above knee amputations, and 13 deaths. All of the revascularization procedures (repeat PTA or vascular bypass operation) treated restenosis at the site of the index lesion. Seven deaths were due to cardiovascular causes, four resulted from malignancy, and two were due to sepsis.

A significant association was documented between preprocedural hemoglobin and both the unadjusted risk of mortality and adverse peripheral vascular outcome (Table II). The unadjusted OR for adverse peripheral vascular outcome, relative to the third tertile preprocedural hemoglobin level was 1.96 (95% CI, 0.68-5.67; P = .21) for the second tertile and 3.18 (95% CI, 1.12-9.04; P = .03) for the first tertile.

Table II. Adverse peripheral vascular outcome according to increasing tertiles of pre-procedural hemoglobin
EventTertile, No. (%)P
1st2nd3rd
Death7(23)4(14)2(6).04
Adverse peripheral vascular outcome18(60)14(48)10(29).03

Cox regression analysis for predictors of adverse peripheral vascular outcome was performed adjusting for age, sex, diabetes mellitus, hypertension, history of smoking, angina, myocardial infarction, stroke, heart failure, renal impairment, Rutherford category, tibial lesion, tibial run-off score >2, and tertiles of hemoglobin concentration (Table III). In addition to diabetes mellitus, renal failure, Rutherford category 5, and poor tibial runoff, preprocedural hemoglobin in the first tertile (OR, 4.17; 95% CI, 1.56-11.16; P = .004) and second tertile (OR, 2.99; 95% CI, 1.14-7.53; P = .03) were independently associated with adverse peripheral vascular outcome. The Figure demonstrates the increased risk in limb amputation or target lesion revascularization for patients with a preprocedular hemoglobin concentration in the first tertile (log-rank test, P = .03). Cox regression analysis also showed that first vs. third tertile of preprocedular haemoglobin was an independent predictor of limb amputation or target lesion revascularization (OR, 5.07; 95% CI, 1.32-19.51; P = .01; Table IV) during the study period.

Table III. Cox regression analysis for predictors of adverse peripheral vascular outcomea
Candidate predictorsOR (95% CI)P
Mean (range)
Rutherford category 54.08(1.44-11.54).008
Diabetes2.95(1.29-6.75).01
Renal Failure3.11(1.32-7.33).009
Preprocedural hemoglobin level
1st vs 3rd tertile4.17(1.56-11.16).004
2nd vs 3rd tertile2.99(1.14-7.53).03
Tibial run-off score >27.98(2.91-21.87)<.0001

CI, Confidence interval; OR, odds ratio.

aVariables included in the model: sex, diabetes mellitus, prior myocardial infarction, heart failure, renal failure, Rutherford category, tibial lesion, tibial run-off score >2, serum creatinine, preprocedural hemoglobin tertiles.

Table IV. Cox regression analysis for predictors of limb amputation or target lesion revascularizationa
Candidate predictorsOR (95% CI)P
Mean (range)
Male gender2.94(2.07-8.08).03
Preprocedural hemoglobin (1st vs 3rd tertile)5.07(1.32-19.51).01
Tibial run-off score >25.13(1.54-17.11).008

CI, Confidence interval; OR, odds ratio.

aVariables included in the model: sex, diabetes mellitus, prior myocardial infarction, heart failure, renal failure, Rutherford category, tibial lesion, tibial run-off score >2, serum creatinine, and preprocedural hemoglobin tertiles.

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Discussion 

Patients with advanced PVD have a high prevalence of anemia that is markedly greater than expected for an elderly population.17, 18 Mild to moderate anemia was associated with an increased risk of mortality and was an independent predictor of adverse peripheral vascular outcome after PTA in patients with Rutherford category 4 or 5 PVD. Procedural hemoglobin in the first tertile was associated with a greater than fourfold increase in risk of adverse peripheral vascular outcome. Furthermore, preprocedural hemoglobin in the first and second tertiles had a greater predictive power of adverse outcome than a history of diabetes. In addition to anemia, tibial vessels runoff score >2 was associated with almost an eightfold increased risk of adverse outcome.

Previous studies have shown procedural anemia to be independently associated with risk of mortality in patients undergoing percutaneous coronary intervention or coronary artery bypass grafting for symptomatic CAD.5, 6, 7 In this study, preprocedural hemoglobin concentration was also an independent predictor of increased risk of limb amputation or target lesion revascularization. This may suggest a role for anemia in the pathophysiology of restenosis following PTA.

Anemia of chronic disease is associated with a low concentration of serum iron. Ferrous iron has been shown to inhibit vascular smooth muscle cell proliferation, which is a critical process in restenosis.19 During the study period, the use of stents was not routine and this could also have contributed to an increased risk of restenosis. In the presence of impaired tissue perfusion after restenosis, decreased oxygen delivery results in continuing tissue ischemia and increased risk of tissue necrosis. This may have contributed to nearly a fifth of our patients requiring definitive surgical treatment in the form of vascular bypass operation or surgical amputation. Anemia is also associated with poor nutritional status, which may be implicated in an increased mortality risk of adverse outcome.20

Correcting hemoglobin concentration <10 g/dL in elderly patients with advanced atherosclerotic disease has been associated with a reduction in mortality.21 A small randomized controlled trial demonstrated a reduction in short-term mortality for heart failure patients with only mild anemia (hemoglobin between 10 and 11.5 g/dL) after receiving subcutaneous erythropoietin and intravenous iron.22 We found that patients with advanced PVD have a high prevalence of anemia, which is also associated with a significantly increased risk of mortality and adverse peripheral vascular outcome. For most patients in the first tertile, preprocedural hemoglobin was higher than the suggested transfusion threshold of 10 g/dL for patients with symptomatic cardiovascular disease.23, 24 This highlights the importance of investigating in this subset of PVD patients whether a higher threshold for correction of anemia could improve on long-term outcome.

Because this was an observational study, we were unable to adjust for unmeasured potential confounding variables. A single preprocedural hemoglobin concentration was recorded, and so it was not possible to account for the effect of procedural related blood loss, which may compound the effect of low preprocedural hemoglobin. The duration of anemia was also unknown.

The use of blood transfusions was not recorded; however, preprocedural hemoglobin for most patients in the first tertile was higher than the transfusion threshold of 10 g/dL suggested for patients with symptomatic cardiovascular disease.

We were not able to report ankle-brachial pressure indices for patients at follow-up because this was not routinely documented in patient notes. Stent use was not routine during the study period, which could have contributed to an increased risk of restenosis.

This study is based on actual clinical practice, and so patients did not have routine follow-up with peripheral angiography. The decision for repeat angiography after the index procedure was determined by recurrence or worsening of clinical symptoms. Therefore, it was not possible to report on patency rates for the index lesion.

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Conclusions 

Anemia is a common comorbid condition in patients with advanced PVD. Preprocedural hemoglobin was associated with an increased risk of mortality and was an independent predictor of long-term adverse peripheral vascular outcome in patients with advanced PVD undergoing nonemergency PTA. This simple and widely available test could be routinely used within clinical practice to risk stratify patients with advanced PVD who are undergoing PTA. Further investigation is needed to determine whether correcting mild preprocedural anemia could improve clinical outcome in patients with advanced PVD.

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Author contributions 


Conception and design: IT, MM, SB

Analysis and interpretation: IT, RJ, SB

Data collection: IT, RJ, MM, SB

Writing the article: IT, RJ, MM, SB

Critical revision of the article: IT, RJ, MM, SB

Final approval of the article: IT, RJ, MM, SB

Statistical analysis: IT, RJ

Obtained funding: Not applicable

Overall responsibility: IT

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 Competition of interest: none.

PII: S0741-5214(09)00773-3

doi:10.1016/j.jvs.2009.03.041

Journal of Vascular Surgery
Volume 50, Issue 2 , Pages 317-321, August 2009

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