Abstract
Background:
Some patients with critical limb ischemia (CLI) lack symptoms of intermittent claudication (IC) before the onset of CLI. We studied the outcome of such patients, because this is currently unknown.
Methods and Results:
For retrospective exploratory analysis, we divided 225 patients (265 limbs) with CLI into 2 groups: 142 patients (172 limbs) without a history of IC (non-IC group) and 83 patients (93 limbs) with IC (IC group). We examined comorbid factors and found that a higher proportion of patients in the non-IC group failed to undergo arterial revascularization (49% vs. 20%, P<0.0001) due to progressed limb ischemia and infection. We then analyzed 140 patients (161 limbs) with revascularization. Patients in the non-IC group were more likely to have diabetes mellitus (P=0.03), hypoalbuminemia (P=0.02), advanced Rutherford’s classification (P=0.0007), worse ambulatory function (P=0.009), and longer postoperative stay (P=0.04). Amputation-free survival was lower in the non-IC group (P=0.005). On Cox regression anlaysis, hemodialysis (P=0.002), coronary artery disease (P=0.04), cerebrovascular disease (P=0.02), non-ambulatory status (P=0.02), and non-IC (P=0.01) were independent risk factors for lower amputation-free survival.
Conclusions:
Patients without IC before CLI onset have several unique features, and non-IC is an independent risk factor for poor outcome. (Circ J 2015; 79: 1618–1623)
There is a subgroup of patients with peripheral artery disease (PAD) who lack symptoms of intermittent claudication (IC) but who develop critical limb ischemia (CLI) even after minor trauma or infection. Those patients with almost critically ischemic arterial blood flow are considered to have chronic subclinical ischemia (CSI) according to the Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease (TASC) II.1
It is possible that the reason such patients have no symptoms despite severe ischemia is because they are sedentary and do not walk far enough to notice IC. Similarly, patients with CSI rarely visit hospitals because they do not complain of any inconvenience. There have been few detailed reports on this subgroup, however, although it is assumed that the number of patients with CSI has increased in recent years. Thus, the present retrospective study investigated patients with CLI who had had no symptoms before onset, in order to clarify the features and clinical outcomes of patients with CSI.
Editorial p 1453
Methods
Patients
This retrospective cohort study was performed according to the guidelines of the research ethics committee of The University of Tokyo Hospital, and all patients provided informed consent for participation. Patients who visited hospital for CLI due to atherosclerosis between 2005 and 2012 were enrolled. CLI was defined as ischemic rest pain, ulcer, or gangrene with objective evidence of ischemia, according to the TASC II definition.1
For the evaluation of CLI, ankle pressure is calculated as the first step of admission, but it is sometimes overestimated due to severe arterial calcification.2,3
Therefore, we also routinely measure skin perfusion pressure (SPP), which is a substitute for toe pressure and can predict wound healing in patients with CLI. In the present study, SPP was considered to be diagnostic for CLI at <40 mmHg.4,5
Contrast-enhanced computed tomography and 3-D angiographic image reconstruction were used to provide an overview of disease distribution in arteries. Thereafter, we performed intra-arterial angiography to determine the strategy for surgery. We sometimes conducted magnetic resonance angiography for patients with chronic renal dysfunction without hemodialysis and with allergy for contrast media.
The following patient clinical characteristics were evaluated: age, sex, hypertension, diabetes mellitus (DM), dyslipidemia, end-stage renal disease with hemodialysis, smoking, antiplatelet use, statin use, and previous history of coronary artery disease (CAD), cerebrovascular disease (CVD), respiratory dysfunction, and physical status (American Society of Anesthesiologists physical status: ASA PS). CAD was defined as >50% stenosis of at least 1 coronary artery or documented diagnosis or intervention for angina or myocardial infarction. CVD was defined as documented stroke or transient ischemic attack. Laboratory data analyzed were hemoglobin and albumin, as well as hemoglobin A1c, ejection fraction measured using transthoracic echocardiography, ankle brachial index, and SPP. Patients were considered to have respiratory dysfunction if they had vital capacity <80% of predicted, or forced expiratory volume in 1s/forced vital capacity ratio <70%. ASA PS was classified as follows: 1, no organ pathology; 2, moderate systemic disease; 3, severe systemic disease; 4, extreme systemic disease that is a threat to life; and 5, emergency that needs the operation for survival. The condition of the affected limbs was assessed according to Rutherford’s classification and the presence of infection. The diagnosis of infection was determined as the presence of local swelling, tenderness, erythema and warmth or obvious purulent discharge.6
On the basis of data obtained from medical records, patients were categorized into 2 groups: those without a history of IC (non-IC group) and those with a previous complaint of IC (IC group). The previous symptom of IC was confirmed on medical interview by physicians, because some patients with CLI had not undergone exercise tolerance tests even though they had had symptoms of IC. Patients whose ambulatory status before the onset of CLI was not described in the medical records, or who had undergone previous surgical revascularization were excluded. Patients with CLI due to Buerger disease, vasculitis secondary to collagen disease or causes other than atherosclerosis were also excluded.
Treatment Strategy and Postoperative Surveillance
Patients with CLI often had accompanying tissue loss and local infection. Immediately after admission, we initiated antibiotic therapy based on white blood cell count and C-reactive protein level. We evaluated patients’ general condition, degree of stenosis or occlusion of the arteries, condition of the patent arteries with sufficient run-off vessels suitable for the anastomotic site, and quality of the autoveins. Endovascular treatment was the first choice for TASC A and B lesions in the iliac region, and bypass surgery for TASC C and D lesions.5
In most patients with infra-inguinal arterial lesions, bypass surgery was performed, and endovascular treatment was adopted only for short-segment lesions in the superficial femoral artery. Generally, we aimed at complete revascularization to the pedal arch, often with aggressive bypass surgery to crural or foot arteries. We occasionally used arm veins or spliced veins. We also performed bypass surgery with conduction anesthesia for patients with extremely poor general condition. Coexisting proximal arterial lesions were also treated. Patients were advised to walk and underwent rehabilitation, if possible. All patients who underwent revascularization were prescribed antiplatelet therapy.
Patients without satisfactory vein grafts (<2.5 mm in diameter), without adequate peripheral arteries for anastomosis, with vital organ dysfunction, and/or with excessive cognitive impairment did not undergo surgery. Primary amputation was considered in cases of massive necrosis or uncontrollable infection. Gangrenous or infectious tissues were sometimes resected simultaneously at the time of operation. After the operation, healthy, uncovered wounds were treated with local recombinant human basic fibroblast growth factor (Fiblast; Kaken Pharmaceutical, Tokyo, Japan) and/or prostaglandin ointment. Vacuum-assisted closure therapy (VAC; Kinetic Concepts, San Antonio, TX, USA) was adapted at times to promote the healing of uncovered wounds.7
Skin graft or free-flap transfer was conducted if all of the aforementioned procedures did not work well to heal wounds. Patients were discharged from hospital after confirmation of surgical wound stability.
Postoperative surveillance was performed with routine physical examinations and ultrasonography for graft patency every 3–6 months in the first 2 years and every 6–12 months afterwards. When the graft was found to be significantly stenosed or occluded, we considered re-intervention for limb salvage. Graft patency, limb salvage rate, survival rate, and amputation-free survival (AFS) were analyzed. Ambulatory function was stratified into 3 levels as follows (Taylor score): 1, fully dependent or bedridden; 2, able to use wheelchair without help; and 3, ambulatory (with a cane).8
Ambulatory status was scored at 2 time points: preoperatively and postoperatively.
Statistical Analysis
All data were analyzed using JMP 9.0 (SAS Institute, Cary, NC, USA). Continuous data are expressed as mean±SD. Chi-squared test was used for categorical data and Student’s t-test for continuous data. Fisher’s exact test was used if any data in the contingency tables were <5. Follow-up results were analyzed using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used for multivariate analysis with adjustment for risk factors. Statistical significance was set at P<0.05.
Results
Of 296 patients (353 limbs) admitted to hospital for CLI between 2005 and 2012, 57 patients (70 limbs) were excluded because the etiology was other than atherosclerosis: Buerger disease, 18 patients (22 limbs); vasculitis secondary to collagen disease, 32 patients (41 limbs); and others, 7 patients (7 limbs). We also excluded 13 patients (15 limbs) who had undergone previous interventions in the IC group: bypass grafting, 4 limbs; percutaneous transluminal angioplasty, 8 limbs; thromboendarterectomy, 2 limbs; and percutaneous transluminal angioplasty and thromboendarterectomy, 1 limb. Three patients (3 limbs) were excluded because their symptoms before the onset of CLI were not recorded. Out of the remaining 225 patients (265 limbs), 142 patients (172 limbs, 65%) belonged to the non-IC group and 83 patients (93 limbs, 35%) to the IC group. The baseline characteristics are summarized in
Table 1. Female sex was more prevalent in the non-IC group, although it did not reach statistical difference (P=0.06). It was noted that the non-IC group had a more advanced limb condition according to Rutherford’s classification (P<0.0001) and infection (P=0.002). In the non-IC group, the reason for revascularization not being performed was as follows: systemic reasons (cardiovascular comorbidity, excessive respiratory dysfunction, malignancy, and/or cognitive impairment) in 36 limbs (42%); local reasons (infection, advanced necrosis, anastomosis unsuitability, and unavailable grafts) in 22 limbs (26%); and others (improvement and patient’s choice) in 27 limbs (32%). In the IC group, systemic factors accounted for non-revascularization in 5 limbs (26%), local factors in 5 limbs (26%), and others in 9 limbs (47%). None of the reasons were statistically different between the non-IC and IC groups (P=0.35). Hence, a higher proportion of patients in the non-IC group could not undergo revascularization compared with patients in the IC group (85 limbs, 49% vs. 19 limbs, 20%; P<0.0001), which was a strong bias for analyzing factors contributing to prognosis, such as AFS.
Table 1.
Baseline Patient Characteristics
| |
Non-IC |
IC |
P-value |
| Patient characteristics |
n=142 |
n=83 |
|
| Age (years) |
70±12 |
71±9 |
0.43 |
| Female gender |
44 (31) |
16 (19) |
0.06 |
| Hypertension |
115 (81) |
68 (82) |
0.86 |
| Diabetes mellitus |
107 (75) |
54 (65) |
0.10 |
| Dyslipidemia |
52 (37) |
23 (28) |
0.17 |
| Hemodialysis |
73 (51) |
40 (48) |
0.64 |
| Smoking |
100 (70) |
63 (76) |
0.37 |
| CAD |
79 (56) |
42 (51) |
0.47 |
| CVD |
39 (27) |
28 (34) |
0.32 |
| Limb characteristics |
n=172 |
n=93 |
|
| Rutherford 4/5/6 |
19/131/22 |
29/61/3 |
<0.0001* |
| Infection |
60 (35%) |
16 (17%) |
0.002* |
| Not revascularized |
85 (49%) |
19 (20%) |
<0.0001* |
Data given as mean±SD or n (%). *P<0.05. CAD, coronary artery disease; CVD, cerebrovascular disease; IC, prior history of intermitten claudication.
After the exploratory analysis for all admitted patients, we then analyzed 140 patients (161 limbs) who underwent revascularization (Table 2). There were more patients with DM (P=0.03) in the non-IC group. In terms of laboratory data, serum albumin was lower in the non-IC group (3.3±0.6 g/dl vs. 3.5±0.5 g/dl, P=0.02). Average SPP was lower in the IC group (23±10 mmHg vs. 18±12 mmHg, P=0.02). Rutherford classification ischemia in the affected limbs was more severe in the non-IC group (P=0.0007). Taylor score of ambulatory function in both the preoperative (P=0.009) and postoperative settings (P=0.0006) was poorer in the non-IC group. Preoperative Taylor score was not affected by the presence of CAD (P=0.62), CVD (P=0.72), or respiratory dysfunction (P=0.10). The distribution of arterial lesions was different between the non-IC and IC group: the non-IC group had fewer arterial lesions in the femoro-popliteal (52 limbs, 60% vs. 61 limbs, 82%, P=0.002) and supra-genicular arteries (59 limbs, 68% vs. 64 limbs, 86%, P=0.005). The demographics of patients undergoing arterial revascularization are also listed in
Table 2. Patients in the IC group received more complex procedures of supra- and infra-inguinal arterial reconstruction (P=0.008). The duration of postoperative hospital stay, however, was longer in the non-IC group (35±28 vs. 28±15 days, P=0.04). There was no 30-day mortality in either group.
Table 2.
Arterial Revascularization Patient Characteristics
| |
Non-IC |
IC |
P-value |
| Patient characteristics |
n=76 |
n=64 |
|
| Age (years) |
69±11 |
71±9 |
0.13 |
| Female |
23 (30) |
13 (20) |
0.18 |
| Comorbidities and laboratory data |
| Hypertension |
65 (86) |
52 (81) |
0.50 |
| Diabetes mellitus |
61 (80) |
41 (64) |
0.03* |
| Dyslipidemia |
31 (41) |
17 (27) |
0.11 |
| Hemodialysis |
42 (55) |
31 (48) |
0.42 |
| Smoking |
57 (75) |
50 (78) |
0.66 |
| CAD |
38 (50) |
31 (48) |
0.85 |
| CVD |
19 (25) |
24 (38) |
0.11 |
| Antiplatelet use |
67 (88) |
58 (91) |
0.64 |
| Statin use |
18 (24) |
18 (28) |
0.55 |
| Hemoglobin (g/dl) |
11.1±1.8 |
11.1±1.7 |
0.78 |
| Albumin (g/dl) |
3.3±0.6 |
3.5±0.5 |
0.02* |
| Hemoglobin A1c (%) |
6.3±1.3 |
6.0±1.0 |
0.16 |
| Ejection fraction (%) |
62±12 |
66±11 |
0.08 |
| Respiratory dysfunction |
31 (41%) |
26 (41%) |
0.98 |
| Affected limbs |
n=87 |
n=74 |
|
| Ankle brachial index |
0.57±0.40 |
0.45±0.31 |
0.06 |
| SPP (mmHg) |
23±10 |
18±12 |
0.02* |
| ASA PS (1/2/3/4/5) |
0/37/48/2/0 |
1/30/42/1/0 |
0.85 |
| Rutherford 4/5/6 |
11/71/5 |
25/49/0 |
0.0007* |
| Infection |
26 (30) |
13 (18) |
0.07 |
| Preoperative status |
| Fully dependent |
6 (7) |
0 (0) |
0.009* |
| Wheelchair |
30 (34) |
17 (23) |
| Ambulatory |
51 (59) |
57 (77) |
| Postoperative status |
| Fully dependent |
6 (7) |
0 (0) |
0.0006* |
| Wheelchair |
31 (36) |
13 (18) |
| Ambulatory |
50 (57) |
61 (82) |
| Distribution of arterial lesions |
| Iliac artery |
15 (17) |
21 (28) |
0.09 |
| Femoro-popliteal artery |
52 (60) |
61 (82) |
0.002* |
| Crural artery |
63 (72) |
47 (64) |
0.23 |
| Supra-genicular artery |
59 (68) |
64 (86) |
0.005* |
| Operation |
| Supra-inguinal arterial reconstruction |
4 (5) |
1 (1) |
0.008* |
| Infra-inguinal arterial reconstruction |
76 (87) |
55 (74) |
| Combination |
7 (8) |
18 (24) |
| Postoperative hospital stay |
35±28 |
28±15 |
0.04* |
Data given as mean±SD or n (%). *P<0.05. ASA PS, American Society of Anesthesiologists physical status; combination, combination of supra- and infra-inguinal arterial reconstruction; infra-inguinal arterial reconstruction, distal bypass and/or femoropopliteal bypass and/or thromboendarterectomy; SPP, skin perfusion pressure; supra-inguinal arterial reconstruction, axillo-femoral bypass or femoro-femoral cross-over bypass or percutaneous transluminal angioplasty for the iliac legion. Other abbreviations as in Table 1.
The mean follow-up period was 35±24 months. Eleven patients (5%) were lost to follow-up. Thus, the follow-up rates at 3 and 5 years were 92% and 92%, respectively. Primary patency was not significantly different between the 2 groups (P=1.00). Secondary patency was favorable in the IC group (P=0.03). Although the limb salvage rate (P=0.15) was not statistically different, the survival rate (P=0.02) and AFS were significantly lower in the non-IC group (P=0.005,
Figure).
As is described in
Table 3, on univariate analysis, hemodialysis (P=0.01), history of CAD (P=0.04), CVD (P=0.04), serum albumin <3 mg/dl (P=0.02), preoperative non-ambulatory status (P=0.0002), and no IC before the onset of CLI (P=0.005) were significant risk factors for low AFS. Given that advanced Rutherford classification (ulcer or gangrene) is a known risk factor for low AFS,9,10
this was also used for adjustment in the multivariate analysis. On Cox proportional hazard model analysis, the following significant risk factors for low AFS were identified: absence of IC before the onset of CLI (hazard ratio [HR], 2.1; 95% confidence interval [CI]: 1.2–3.8; P=0.01); hemodialysis (HR, 2.3; 95% CI: 1.3–3.9; P=0.002), history of CAD (HR, 1.7; 95% CI: 1.0–2.9; P=0.04), CVD (HR, 2.0; 95% CI: 1.1–2.3; P=0.02) and preoperative non-ambulatory status (HR, 1.9; 95% CI: 1.1–3.2; P=0.02;
Table 3).
Table 3.
Risk Factors for AFS in Arterial Revascularization Patients
| |
Univariate |
Multivariate |
| P-value |
HR |
95% CI |
P-value |
| Age >65 years |
0.27 |
|
|
|
| Female gender |
0.38 |
|
|
|
| Hypertension |
0.61 |
|
|
|
| Diabetes |
0.38 |
|
|
|
| Dyslipidemia |
0.91 |
|
|
|
| Hemodialysis |
0.01* |
2.3 |
1.3–3.9 |
0.002* |
| Smoking |
0.73 |
|
|
|
| CAD |
0.04* |
1.7 |
1.0–2.9 |
0.04* |
| CVD |
0.04* |
2.0 |
1.1–3.3 |
0.02* |
| Non-IC |
0.005* |
2.1 |
1.2–3.8 |
0.01* |
| Albumin <3 mg/dl |
0.02* |
1.7 |
0.93–3.0 |
0.09 |
| Non-ambulatory |
0.0002* |
1.9 |
1.1–3.2 |
0.02* |
| Infection |
0.24 |
|
|
|
| Rutherford 5 or 6 |
0.81 |
0.53 |
0.29–1.0 |
0.05 |
*P<0.05. AFS, amputation-free survival; HR, hazard ratio. Other abbreviations as in Table 1.
Discussion
Asymptomatic PAD accounts for approximately 20–60% of all PAD cases according to reports from population-based or primary care settings.11,12
Previously, asymptomatic PAD was misunderstood to be benign.3,11
Recent studies, however, found that the survival and cardiovascular or cerebrovascular event rates between symptomatic and asymptomatic PAD are not different.13,14
Furthermore, Diehm et al reported no differences in the peripheral amputation rate between asymptomatic and symptomatic PAD patients in a primary care setting.13
Unlike these reports, the present study compared a non-IC group and IC group, both of which presented with CLI on admission, and it was found that the classification of clinical symptoms, such as Fontaine’s classification, is not sufficient to evaluate the progression of PAD or the worse prognosis for the non-IC group.
Considering the recent drastic increases in the number of patients with DM, we hypothesized that the non-IC group would include more patients with diabetic neuropathy who were insensible to ischemic pain compared with patients in the IC group. Although the diagnosis of diabetic neuropathy was not confirmed in all patients, sensory nerve disorder would be a likely explanation for the absence of IC in the non-IC group. In the present study, the prevalence of DM was significantly higher in the non-IC group with arterial revascularization compared with that of the IC group. This hypothesis is also supported by the fact that there were fewer patients in the non-IC group who were categorized as Rutherford 4. Diabetic neuropathy would be one of the reasons why non-IC patients often presented with foot ulcers or gangrene at first. Moreover, the present non-IC group was characterized by more advanced limb condition. Adverse limb condition led to the failure of patients in the non-IC group to undergo revascularization surgery. It is possible that patients in the non-IC group did not consult doctors because they have no inconvenience. As a result, they were not aware of risk factor modification or advice for (home-based) exercise therapy. Advanced limb condition in the non-IC group may be due to delay in hospital admission. Another characteristic of the non-IC group was the distal distribution of arterial lesions, which would also explain the absence of IC before the onset of CLI. Because the imbalance of the proportion of revascularized patients was a strong selection bias in the analysis of long-term outcome, we limited the analysis to include only patients with revascularization.
Our second hypothesis was that ambulatory function was associated with poorer outcome in the non-IC group. In fact, more patients in the non-IC group receiving revascularization were bedridden, used a wheelchair, or did not walk long distances. The poor ambulatory function, however, had not resulted from a prior history of CVD or cardiopulmonary dysfunction; it was instead attributable to the musculoskeletal characteristics of patients in the non-IC group. McDermott et al, who compared symptomatic and asymptomatic PAD patients, found that a lack of exertional leg symptoms correlated with poor functional performance.15
Such patients may not feel muscular discomfort induced by exercise, and so may often not consult a physician until their limbs develop an ulcer or gangrene, in contrast to claudicants, who have pain signals that cause them to consult a doctor. Non-ambulatory status was a significant risk factor for AFS on multivariate analysis in the present study, in accordance with the previous studies that found that patients with impaired ambulatory function have extensive comorbid conditions, high adverse event rates, repeated re-interventions, and poor survival rates.16–18
Functional status may therefore be an important feature of the non-IC group.
Although it did not reach a statistical difference, female sex was another characteristic of the non-IC group (Tables 1,2). Numerous papers have noted worse outcome for women with PAD compared with men with PAD,19–21
because female patients with PAD were reported to have more severe and diffuse below-the-knee lesions than do men.20,21
Therefore, female sex should be noted in future studies on patients with CSI.
On multivariate analysis it was determined that hemodialysis, CAD, CVD, non-ambulatory status, and absence of history of IC were factors influencing AFS. Hemodialysis, CAD and non-ambulatory status are known prognostic factors for PAD.1,8,16
In contrast, CVD is rarely reported as an adverse factor for CLI outcome.22
It is convincing, however, that the presence of CVD in patients with CLI is predictive of mortality, considering that the coexistence of the 2 diseases means polyvascular disease.23
This study had some limitations. First, this was a single-center retrospective study. Second, given that The University of Tokyo Hospital is a tertiary medical center, there is referral filter bias. Patients with massive necrosis or infection who needed urgent amputation were excluded automatically. Although the non-surgical patients were excluded after the exploratory analysis of all CLI patients to limit selection bias, several confounding factors would still exist. Ideally, a prospective longitudinal study should be used to determine the prognostic factors for CSI.
Conclusions
We examined patients without a history of IC before the onset of CLI to determine the unique features of patients with CSI. Upon admission, they presented with more progressed limb ischemia and infection. As a result, half of them failed to undergo arterial revascularization. The revascularized patients in the non-IC group were more likely to have DM, hypoalbuminemia, worse limb condition, worse ambulatory function, and longer postoperative stay. Non-IC patients had fewer arterial lesions in the supra-genicular arteries. Hemodialysis, CAD, CVD, preoperative non-ambulatory status, and no IC before the onset of CLI were predictors of low AFS. The fact that non-IC was an independent risk factor for poor outcome in patients with CLI highlights the need to identify asymptomatic patients at high risk for CLI: that is, patients with CSI. Further prospective longitudinal studies are necessary to elucidate the unique features of patients with CSI.
Disclosures
Conflict of Interest: There is no conflict of interest to declare. Name of Grant: None.
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