Predictors of 2-Year Mortality and Risk Stratification After Surgical or Endovascular Revascularization of Infrainguinal Artery Disease in Hemodialysis Patients With Critical Limb Ischemia

Abstract

Purpose: To examine the 2-year mortality in hemodialysis (HD) patients with critical limb ischemia (CLI) and determine predictors that may aid in the selection of a revascularization strategy [bypass surgery or endovascular therapy (EVT)] according to current guidelines. Methods: From 2007 to 2009, 246 consecutive CLI patients (mean age 69±10 years; 170 men) on HD underwent revascularization for de novo infrainguinal lesions (178 EVT and 68 bypass grafting). The majority of the patients had diabetes (170, 69%) and tissue loss (194, 79%); nearly half (111, 45%) were nonambulatory. Overall survival after revascularization was estimated by Kaplan-Meier analysis. Predictors for 2-year mortality after revascularization were determined using a Cox proportional hazards model; results are given as the hazard ratio (HR) and 95% confidence interval (CI). Results: Overall survival rate was 77% at 1 year and 66% at 2 years. Predictors of 2-year mortality after revascularization were age >75 years (HR 1.82, 95% CI 1.14 to 2.91, p=0.012), albumin <3 g/dL (HR 2.31, 95% CI 1.39 to 3.84, p=0.001), and ejection fraction <50% (HR 1.73, 95% CI 1.06 to 2.83, p=0.027). Patients with more predictors had a higher incidence of death within 2 years after revascularization. Conclusion: Advanced age, low albumin level, and low ejection fraction were independently associated with 2-year mortality after revascularization in HD patients with CLI. Risk stratification by these factors would be useful for deciding on a revascularization strategy.

Keywords

critical limb ischemia hemodialysis infrainguinal disease stenosis occlusion endovascular therapy bypass surgery bypass graft mortality

Introduction

The number of patients with end-stage renal disease on hemodialysis (HD) has been increasing.¹ Currently numbering more than 2 million worldwide, patients on HD generally have multiple systemic comorbidities, and their arteries are affected by severe calcification leading to critical limb ischemia (CLI), the most severe manifestation of lower extremity peripheral artery disease (PAD).² Revascularization is the optimal treatment for patients with CLI³; however, HD patients with CLI have worse clinical outcomes after endovascular therapy (EVT) or bypass surgery (BSG) than patients without HD.^4,5

BASIL, the only randomized trial comparing the EVT-first vs BSG-first strategies in CLI patients, showed similar 2-year rates of amputation-free and overall survival between EVT and BSG.⁶ Based on BASIL, patients with >2-year life expectancy and available vein were better candidates for BSG because of the good long-term durability of vein grafts, while EVT would be preferable if the patient is expected to live <2 years, as they would not reap the long-term benefits of surgery.^7,8

Predictors of 2-year mortality after revascularization in HD patients with CLI would inform decision making regarding revascularization strategy. We therefore investigated predictors of 2-year mortality and risk stratification by the number of these predictors after surgical or endovascular revascularization for HD patients with CLI due to infrainguinal artery disease.

Methods

Registry Design

This multicenter retrospective registry involved 8 Japanese institutions whose prospectively maintained databases were interrogated to identify all consecutive HD patients with CLI undergoing a first EVT or BSG for infrainguinal artery disease between January 2007 and December 2009. One limb was included per enrolled patient. Patients who underwent conservative treatment or primary amputation and patients with aortoiliac lesions or acute limb ischemia were excluded. A group of vascular specialists, including vascular surgeons and radiologists, judged whether EVT or BSG was indicated for each patient. This judgment was left to the discretion of each institution. All data were entered at the time of first admission, and the registry was updated periodically with patient follow-up data. Study participants at all institutions were generally followed at 1, 3, 6, 12, and 24 months after BSG or EVT. If a patient did not return to the hospital, limb status and the patient’s general health were checked via phone interview.

Endovascular Procedure

Endovascular therapy was performed under local anesthesia. In femoropopliteal lesions, angioplasty was initially performed. If the post balloon result was suboptimal, a nitinol stent was provisionally implanted. For infrapopliteal lesions, balloon angioplasty was performed with an optimally sized balloon, commonly >200 mm long, and with balloon inflation held at nominal pressure for at least 180 seconds to avoid flow-limiting dissection.⁹ Dual antiplatelet therapy [aspirin (100 mg/d) and clopidogrel (75 mg/d) or ticlopidine (200 mg/d) or cilostazol (200 mg/d)] was started at least 1 week prior to EVT and continued lifelong. Medical treatment was left to the doctor’s discretion.

Bypass Surgery Procedure

Bypass surgery was performed under general anesthesia using standard techniques with an autogenous vein graft. The vein was harvested, flushed with heparinized saline solution, and reversed. Prosthetic vascular grafts were used in cases without appropriate usable autogenous vein. Postprocedure medication was selected according to local clinical practice.

Definitions

Critical limb ischemia was defined in accordance with the TransAtlantic Inter-Society Consensus II (TASC II) guidelines as tissue loss or rest pain due to chronic ischemia associated with ankle pressure <70 mm Hg or a toe pressure <50 mm Hg.³ When these measurements could not be obtained, skin perfusion pressure (SPP) was measured for evaluation of ischemia. SPP (Sensilase PAD 3000; Väsamed, Eden Prairie, MN, USA), which reflects skin perfusion status or skin capillary blood pressure, was regularly measured at the dorsal and plantar sides of the foot; an ischemic limb was indicated by a SPP <40 mm Hg.¹⁰ Severity of CLI was determined according to the Rutherford classification.¹¹ Lesion severity was classified according to TASC II after evaluation by aortography or computed tomographic angiography.³

Nonambulatory status was regarded as wheelchair use or being bedridden. Diabetes mellitus was based on World Health Organization criteria or on having been treated with insulin and/or oral hypoglycemic agents. Coronary artery disease (CAD) was defined as stable angina with documented CAD, history of percutaneous coronary intervention, coronary artery bypass graft surgery, or previous myocardial infarction. Ejection fraction was evaluated by transthoracic echocardiography.

Major amputation was defined as amputation above the ankle. Perioperative death was defined as death within 30 days after revascularization. Repeat revascularization was clinically driven by delayed wound healing or rest pain recurrence; SPP <40 mm Hg was used as the standard criterion for any repeat revascularization.

Registry Participants

A total of 246 consecutive CLI patients (mean age 69±10 years; 170 men) on dialysis were included in the current study; their baseline characteristics are shown in Table 1. The majority of patients (194, 79%) had tissue loss; 52 (21%) patients had CLI in the contralateral limb. The mean time from the initiation of dialysis to CLI onset was 5.2±4.8 years (data available in 108 cases). Diabetes was prevalent in the population (170, 69%).

Table 1.

Baseline Characteristics of the 246 Study Patients.^a

Patient Characteristics
Age, y	69±10
>75	65 (26)
Men	172 (70)
Body mass index, kg/m²	21±3
<18.5	60 (24)
Nonambulatory status	111 (45)
Risk factors
Diabetes mellitus	170 (69)
Coronary artery disease	146 (59)
Ejection fraction	59±14
<50%	53 (22)
Laboratory data
Albumin, g/dL	3.4±0.5
<3 g/dL	46 (19)
Limb/lesion characteristics
Rutherford category 4/5/6	52 (21) / 164 (67) / 30 (12)
TASC II classification
Femoropopliteal lesions	152 (61)
A/B/C/D	29/43/45/35
Infrapopliteal lesions	191 (77)
A/B/C/D	1/8/11/171

Abbreviation: TASC: TransAtlantic Inter-Society Consensus.

Continuous data are presented as the means ± standard deviation; categorical data are given as the counts (percentage).

The initial treatment strategy is summarized in Table 2. Surgical bypass or EVT was performed in 68 (28%) and 178 (72%) patients, respectively. Among those undergoing EVT, stents were implanted in 72 (64%) of 112 limbs with femoropopliteal lesions. BSG with autogenous vein graft was feasible in 60 (88%) of 68 limbs.

Table 2.

Revascularization Strategies in 246 Study Patients.^a

Endovascular therapy	178 (72)
Femoropopliteal	40 (16)
Femoropopliteal and tibial	72 (29)
Tibial artery	66 (27)
Bypass grafting	68 (28)
Femoropopliteal AK
Autogenous vein	2 (1)
ePTFE	5 (2)
Femoropopliteal BK autogenous vein	3 (1)
Femorotibial autogenous vein	19 (8)
Popliteal (AK)-tibial
Autogenous vein	16 (7)
ePTFE	3 (1)
Popliteal (BK)-tibial autogenous vein	20 (8)

Abbreviations: AK, above knee; BK, below knee; ePTFE, expanded polytetrafluoroethylene.

Data are given as the counts (percentage).

Outcome Measure and Statistical Analysis

Data are expressed as mean ± standard deviation for continuous variables or as count (percentage) for dichotomous variables unless otherwise noted. Categorical variables were compared with the Fisher exact test.

The outcome measure was overall survival after revascularization. Estimates of overall survival, major amputation, and repeat revascularization were assessed using the Kaplan-Meier method; differences in the estimates for EVT vs BSG were examined with the log-rank test.

A multivariate Cox proportional hazard model with the stepwise method was used to determine independent risk factors for 2-year mortality after revascularization using EVT, age >75 years, male gender, body mass index <18.5 kg/m², nonambulatory status, Rutherford category, diabetes mellitus, albumin <3 g/dL, ejection fraction <50%, and CAD as covariates.^12–14 Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported. Risk stratification of 2-year mortality was based on a risk score, which was developed by counting the number of these risk factors. The threshold of statistical significance was p<0.05. Statistical analyses were performed with SPSS software (version 15.0J; IBM Corporation, Somers, NY, USA).

Results

Clinical Outcomes After Revascularization

Two-year follow-up was completed in 198 (80%) of the 246 patients. Mean follow-up was 23 months (range 0–58). During the observation period, 76 patients died from cardiac disease (27, 36%), followed by infection (19, 25%), vascular disease (11, 14%) [including cerebrovascular disease (7) and bowel ischemia (4)], and severe bleeding (4, 5%). Death within 30 days was observed in 5 (3%) of 178 patients in the EVT group and 6 (9%) of the 68 patients in the BSG group (p=0.076). The cause of death after EVT was infection (2), gastrointestinal bleeding (2), and cardiac causes (1) compared to infection (4) and stroke (2) in the BSG cohort.

Overall survival rates after revascularization were 77% at 1 year and 66% at 2 years (Figure 1). Survival rates up to 2 years did not differ significantly after EVT vs BSG (69% vs 58%, p=0.182). Rates of freedom from major amputation at 1 and 2 years were 88% and 85% in the EVT group and 86% and 82% in the BSG groups, respectively (p=0.359). Rates of repeat intervention (repeat EVT or surgical reconstruction) at 1 and 2 years were 35% and 43% in the EVT group and 29% and 34% in the BSG group, respectively (p=0.348).

Predictors of 2-Year Mortality and Risk Stratification

As shown in Table 3, univariate analysis revealed a significant association of 2-year mortality with the following variables: age >75 years, nonambulatory status, serum albumin level <3 g/dL, and ejection fraction <50%. In the multivariate model, age >75 years (HR 1.82, 95% CI 1.14 to 2.91, p=0.012), serum albumin level <3 g/dL (HR 2.31, 95% CI 1.39 to 3.84, p=0.001), and ejection fraction <50% (HR 1.73, 95% CI 1.06 to 2.83, p=0.027) were independent risk factors of 2-year mortality after revascularization. Figure 2 shows that 2-year mortality rate after revascularization varied according to number of risk factors, with higher 2-year mortality rates for the higher score groups.

Table 3.

Univariate and Multivariate Analysis of 2-Year Mortality After Revascularization in Patients With Critical Limb Ischemia.

Variables	Univariate Model^a	Multivariate Model^a
Endovascular therapy	0.69, 0.43 to 1.11, p=0.135	0.71, 0.44 to 1.14, p=0.167
Age >75 y	1.95, 1.23 to 3.10, p=0.005	1.82, 1.14 to 2.91, p=0.012
Male gender	1.14, 0.70 to 1.88, p=0.581	—
Body mass index <18.5 kg/m²	1.42, 0.87 to 2.32, p=0.156	—
Nonambulatory status	1.71, 1.09 to 2.69, p=0.019	—
Tissue loss (vs Rutherford 4)
Rutherford 5	1.51, 0.91 to 2.50, p=0.104	—
Rutherford 6	1.27, 0.67 to 2.40, p=0.461	—
Diabetes mellitus	0.95, 0.59 to 1.53, p=0.852	—
Albumin <3 g/dL	2.64, 1.61 to 4.34, p<0.001	2.31, 1.39 to 3.84, p=0.001
Ejection fraction <50%	1.81, 1.12 to 2.94, p=0.015	1.73, 1.06 to 2.83, p=0.027
Coronary artery disease	1.21, 0.76 to 1.93, p=0.414	—

Data are given as the hazard ratio, 95% confidence interval, p value.

Discussion

In the clinical setting of CLI patients on HD, the numerous comorbidities render it difficult to decide on treatment strategy. Identification of prognostic factors and estimation of life expectancy for these patients are therefore clinically relevant. The current study confirmed that advanced age was an independent predictor for 2-year mortality in HD patients with CLI. The PREVENT III trial, in which 12% of the study population received HD, previously demonstrated an independent association of age with 2-year mortality.¹⁴ The finding was also consistent with a previous report by Bernard et al,¹³ who investigated predictors of mortality for HD patients with PAD. In general, advanced age is often accompanied by an increased number of comorbidities and is more likely associated with a shortened life expectancy. Our findings suggest that the association of aging with mortality is true for HD patients with CLI, who are expected to have an extremely poor prognosis.

In our study, ejection fraction <50% assessed by ultrasound examination as an indicator of cardiac dysfunction was identified as another strong independent predictor of 2-year mortality after revascularization. However, unlike previous reports,^13,14 a past medical history of CAD was not identified as an independent predictor. One possible explanation might be a high proportion of heart failure. In the current study population, cardiac death was the leading cause of death, and chronic heart failure accounted for as much as 85%, while acute coronary syndrome accounted for only 4%. The reason why cardiac function rather than CAD history surfaced as a risk factor might reflect these characteristic outcomes in HD patients with CLI. The current study did not assess severity of CAD, although previous studies suggested a significant association with mortality.^15,16 Further investigation on whether a low ejection fraction remains an independent predictor for mortality after adjustment for severity of CAD is warranted.

Low serum albumin level was also found to be one of the prognostic factors in the current study. The finding is consistent with a previous report in HD patients with PAD¹³ and the strong association between mortality and albumin level in HD patients documented in several previous reports.^17,18 In general, prevalence of albumin <3 g/dL was reported to be only 2% to 3% in HD patients.^19,20 On the other hand, prevalence of albumin <3 g/dL was as high as 22% in our study. This observation suggests that HD patients with CLI have poorer nutrition status than HD patients overall. Given its high prevalence in this setting, albumin <3 g/dL could not be a negligible risk factor in discussion of life expectancy in HD patients with CLI.

A long history of dialysis has been recognized as a classical prognostic risk factor for patients on regular hemodialysis.²¹ Information on time from initiation of dialysis to vascular intervention was available in less than half (44%) of the study patients. In multivariate analysis, HD duration (1-year increments) was an independent predictor for mortality (HR 1.06, 95% CI 1.01 to 1.12). Further examination of dialysis duration is warranted.

According to accepted guidelines,²² life expectancy <2 years is the main determinant in revascularization modality selection, that is, either BSG or EVT, in patients with CLI. The current determination of independent risk factors for 2-year mortality in HD patients with CLI would enable appropriate risk stratification and therefore appropriate selection of revascularization strategy in the population.

Limitations

This study was a retrospective analysis of prospectively maintained databases. Patients without revascularization were excluded, and the population of patients treated with primary amputation was not examined. Only Japanese patients were included in this study; therefore, it remains to be seen whether this predictive model would allow an appropriate risk stratification of CLI patients with HD in other ethnic groups. Selection bias is a limitation in this study; indications for treatment and selection of EVT or BSG were not standardized and were left to the discretion of each institution.

Conclusion

Advanced age, low ejection fraction, and low albumin level were independently associated with 2-year mortality after surgical or endovascular revascularization in HD patients with CLI. Risk stratification by these risk factors would be useful in informing decision making on revascularization strategy.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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