Long-Term Prognosis of Diabetic Patients With = Critical=20 Limb Ischemia

A population-based cohort study

¹Diabetology Center, Diabetic Foot Center, = Istituto Di=20 Ricovero e Cura a Carattere Scientifico (IRCCS) Multimedica, Sesto San = Giovanni, Milano, Italy;
²Interventional Radiology Laboratory, IRCCS = Multimedica,=20 Sesto San Giovanni, Milano, Italy;
³Vascular Surgery Unit, University of Milan, = Milan, Italy;=20
⁴Medical Statistics Unit, University of Milan, = Milan,=20 Italy.

Corresponding author: Giacomo = Clerici, giacomo.clerici{at}multimedica.it =

Abstract

OBJECTIVE To evaluate the long-term = prognosis of=20 critical limb ischemia (CLI) in diabetic patients.

RESEARCH DESIGN AND METHODS A total of 564=20 consecutive diabetic patients were hospitalized for CLI from January = 1999 to=20 December 2003; 554 were followed until December 2007.

RESULTS The mean follow-up was 5.93 =C2=B1 = 1.28 years.=20 Peripheral angioplasty (PTA) was performed in 420 (74.5%) and bypass = graft (BPG)=20 in 117 (20.6%) patients. Neither PTA nor BPG were possible in 27 (4.9%)=20 patients. Major amputations were performed in 74 (13.4%) patients: 34 = (8.2%) in=20 PTA, 24 (21.1%) in BPG, and 16 (59.2%) in a group that received no=20 revascularization. Restenosis occurred in 94 patients, bypass failures = in 36=20 patients, and recurrent ulcers in 71 patients. CLI was observed in the=20 contralateral limb of 225 (39.9%) patients; of these, 15 (6.7%) required = major=20 amputations (rate in contralateral compared with initial limb, = P =3D=20 0.007). At total of 276 (49.82%) patients died. The Cox model showed = significant=20 hazard ratios (HRs) for mortality with age (1.05 for 1 year [95% CI = 1.03=E2=80=931.07]),=20 unfeasible revascularization (3.06 [1.40=E2=80=936.70]), dialysis (3.00 = [1.63=E2=80=935.53]),=20 cardiac disease history (1.37 [1.05=E2=80=931.79]), and impaired = ejection fraction (1.08=20 for 1% point [1.05=E2=80=931.09]).

CONCLUSIONS Diabetic patients with CLI have = high=20 risks of amputation and death. In a dedicated diabetic foot center, the = major=20 amputation, ulcer recurrence, and major contralateral limb amputation = rates were=20 low. Coronary artery disease (CAD) is the leading cause of death, and in = patients with CAD history the impaired ejection fraction is the major=20 independent prognostic factor.

A variety of consensus statements and reviews (1=E2=80=933) have=20 assessed the outcomes of diabetic patients with peripheral arterial = disease=20 (PAD). However, we are not aware of any prospective studies performed in = a=20 diabetic population with critical limb ischemia (CLI). The aim of this=20 prospective study was to evaluate in diabetic patients the prognostic = impact of=20 CLI diagnosed according to the criteria proposed in 2000 by the = Transatlantic=20 Inter-Society Consensus (TASC) (4).

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RESEARCH DESIGN AND METHODS

Between 1 January 1999 and 31 December 2003, 564 diabetic = patients=20 were hospitalized in our diabetic foot center because of CLI. During the = hospital stay, patients and their families were trained to manage both = an=20 ulcerated and a nonulcerated foot. The importance of prompt immediate = referral=20 to our center, irrespective of scheduled visits, was pointed out in = cases of=20 insurgence of ischemic rest pain or ulcerations, even of minimal = appearance. All=20 patients who underwent peripheral revascularization were prescribed = either 250=20 mg/day ticlopidine plus 100 mg/day salicylic acid or 500 mg/day = ticlopidine.=20

CLI diagnosis

All diabetic patients referred to our diabetic foot center = for=20 ischemic rest pain and/or foot ulcer or gangrene were assessed for the = presence=20 of sensory motor neuropathy, infection, and CLI. Sensory motor = neuropathy was=20 diagnosed in patients with a biothesiometer vibration perception = threshold=20 >25 V, insensitivity to touching with a Semmes-Weinstein 10-g = filament in=20 >5 of 9 foot points, and absence of the Achilles tendon reflex. In = patients=20 with foot ulcers, the presence of an infection was indicated by local=20 cellulitis, erythema, or purulence with a positive swab culture. CLI was = diagnosed in patients with <70 mmHg ankle pressure, when assessable, = and=20 <50 mmHg transcutaneous oxygen tension (TcPO₂) at the = dorsum of=20 the foot.

Vascular procedures

All patients with CLI were referred to an angiographic = study. Patients=20 with vessel diameter obstruction >50% underwent peripheral = angioplasty (PTA)=20 during the angiographic study, when possible, as a first-choice=20 revascularization procedure (PTA group) (5). PTA=20 was utilized extensively: no stenosis or occlusion was considered a = priori=20 unsuitable for a PTA recanalization. Stenoses or occlusions >10 cm in = length=20 and consecutive multiple stenoses (types C and D of the TASC = morphological=20 stratification of obstructions) were treated with PTA when possible; PTA = was not=20 feasible when calcified vessel occlusions did not permit passage of a = balloon=20 catheter. Vessel recanalization was considered successful when direct = flow was=20 achieved in at least one artery down to the foot and that had no = significant=20 residual stenoses along the entire artery.

When PTA was not feasible, a bypass graft (BPG) was = considered (BPG=20 group). BPG was performed using an intraluminal clamping and = microsurgical=20 technique. The autogenous saphenous vein was used for grafting when = present and=20 in good condition. When it was not available, alloplastic prosthetic = material=20 (polytetrafluoroethylene [PTFE]) was utilized and the peripheral = anastomosis=20 consisted of a venous cuff. Thus, the absence of an available saphenous = vein and=20 an angiographic score run off >7 on the Rutherford scale (6) did=20 not exclude patients from a revascularization with a distal bypass; = otherwise,=20 the only recourse for those patients would have been a major amputation. = When=20 neither PTA nor BPG were possible, patients received prostanoid therapy = (60=E2=80=93120=20 =CE=BCg/day alprostadil-=CE=B1-ciclodextrine) over a period of 5 days = after the=20 angiography.

Hemodynamic improvement

TcPO₂ values were reassessed 5=E2=80=9310 days = after the PTA, BPG,=20 or prostanoid infusion.

End points

The following end points were recorded: above-the-ankle = amputation,=20 ulcer recurrence, clinical restenosis after PTA, BPG failure, CLI, major = amputation in the contralateral limb, and survival.

Amputation

Limb salvage was considered successful when the plantar = stance was=20 maintained, even when achieved by tarsal-metatarsal amputation (7).=20 Conversely, any above-the-ankle amputation was considered a major = amputation,=20 and it was deemed a failure. It was performed when therapies did not = relieve=20 patients from resting pain or when gangrene had extended beyond the = Chopart=20 joint.

Restenosis after PTA

Restenosis was suspected when ischemic rest pain reappeared = or an=20 ulcer worsened or did not heal. In these situations, ankle pressure and=20 TcPO₂ were reassessed and duplex scanning was performed (8). If=20 ankle pressure and TcPO₂ again showed values diagnostic for = CLI and=20 had significantly deteriorated (<15% of the post-PTA value) and = Duplex=20 scanning was positive, a further PTA was performed. When a PTA was not = possible,=20 a BPG was considered. Morphological restenoses were not investigated; we = did not=20 perform revascularizations in the absence of ischemic resting pain or=20 ulcerations; therefore, we considered morphological restenoses = clinically=20 irrelevant (9).

BPG failure

Vascular surgeons assessed graft patency by ultrasonography = at 30=20 days; 3, 6, and 12 months; and every 6 months thereafter (10= ).=20

Ulcer recurrence

The reappearance of a foot lesion after the primary ulcer = had healed=20 was considered an ulcer recurrence.

Vital status and cause of death

The vital status of all 554 patients was determined at the = end of=20 follow-up. Dates and causes of deaths were recorded. All patients in our = study=20 population had been referred to our diabetic foot center from other = diabetes=20 centers. After admission due to CLI, they were moved to the originating = diabetes=20 center for diabetologic and comorbid condition treatments.

Database

The database records included age, sex, diabetes treatment = and=20 duration, glycemia (finger-stick glucose) at entry and discharge, A1C = (with=20 high-pressure liquid chromatography; normal value 4=E2=80=936.4%), = albumin excretion=20 (mg/24 h; nephelometry; Behring, Scopito, Italy), serum creatinine value = (mg/dl,=20 Jaffe; Roche, Milan, Italy), arterial hypertension (antihypertensive = treatment),=20 history of cardiac disease, ejection fraction (evaluated with = transthoracic=20 echocardiography in patients with a history of cardiac disease), history = of=20 stroke, and history of prior major amputation.

Statistical methods

Data were given as average values and SDs for continuous = variables or=20 as percentages for discrete variables. We explored the role of = continuous=20 variables across the treatment groups with the Student's t test = and=20 ANOVA. The presence of prognostic factors was assessed with the = =CF=87²=20 test with Yate's correction. The 95% CI was adopted, and 5% was = considered=20 significant for the null hypothesis. The proportion of surviving = patients was=20 plotted with a Kaplan-Meier curve, and differences in survival among = subgroups=20 were tested by the log-rank test. Cox's proportional hazards model was = used to=20 select significant prognostic factors. Proportionality among the = survival rates=20 and attributable factors in the Cox model was assessed by plotting the = log(=E2=88=92log=20 [survival function]) versus time in each subgroup. The significant role = of=20 covariates was measured with the likelihood ratio test, and the role of = each=20 covariate entering the model was assessed by the Wald statistic. = Statistical=20 analyses were performed with STATA 9.0 for Windows. Analysis of survival = was=20 carried out on an intention-to-treat basis.

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RESULTS

Of the initial 564 patients, 554 (98.2%) were followed = until 31=20 December 2007 for a mean of 5.93 =C2=B1 1.28 years. Of the 554 followed = patients, 413=20 (74.5%) underwent PTA and 114 (20.6%) underwent BPG in the initially = affected=20 limb. In the remaining 27 (4.9%) patients, neither PTA nor BPG could be=20 performed (nonrevascularized patients).

Demographics and clinical characteristics of the three = groups are=20 reported in Table = 1.=20 The ankle pressure could not be measured in 297 (53.6%) patients due to = the=20 occlusion of both tibial arteries in 105 and due to the presence of = arterial=20 calcifications in 192 patients (11= ).=20 Toe pressure could not be measured in 89 patients due to a previous = amputation=20 or gangrene on the big toe. Thus, ankle and toe pressure parameters were = not=20 considered in the data analysis.

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Table 1=20

Demographic and clinical = characteristics of study=20 population (n =3D 554) at the study entry in nonrevascularized = and=20 revascularized patients with PTA or BPG

PTA was performed in 413 (74.5%) patients. In these = patients,=20 angiography revealed obstructions >50% of vessel diameter exclusively = located=20 in the iliac-femoral-popliteal axes in 28 patients (6.8%) and = exclusively=20 located in the infrapopliteal axis in 137 subjects (32.2%). Obstructions = were=20 found in both the iliac-femoral-popliteal and infrapopliteal axes in 248 = patients (60.0%). The mean TcPO₂ values were 15.3 =C2=B1 11.9 = mmHg before=20 and 44.9 =C2=B1 12.1 mmHg after PTA (P < 0.001). A BPG was = performed in=20 114 (20.6%) patients. The Rutherford grading for runoff was 6.4 =C2=B1 = 2.6. The BPG=20 was axillo-femoral in one patient, femoral-popliteal (15 PTFE, 44 vein = graft) in=20 58 patients, and femoral-infrapopliteal (16 PTFE, 39 vein graft) in 55 = patients.=20 The mean TcPO₂ values were 10.2 =C2=B1 10.3 mmHg before and = 38.8 =C2=B1 11.9=20 mmHg after BPG (P < 0.001).

Neither a PTA nor a BPG was possible in 27 (4.8%) patients = due to=20 high surgery risk (7 patients) or lack of outflow (20 patients). These = patients=20 received prostanoids treatment for 5 days during the hospital stay after = angiography. The average TcPO₂ values were 7.0 =C2=B1 8.1 = mmHg before and=20 11.4 =C2=B1 8.6 mmHg after prostanoid treatment (P =3D 0.055). = After=20 revascularization, no significant difference was observed in the=20 TcPO₂ values for the PTA and BPG groups (P =3D = 0.690). In=20 contrast, a significant difference was observed between revascularized = and=20 nonrevascularized patients (P < 0.001).

Minor amputation

A total of 440 revascularized patients with foot ulcers = showed=20 complete healing of the lesions: 93 patients did not receive any minor=20 amputations (35 patients by means of foot dressings, 12 bone removals, = 16=20 ulcerectomies, and 30 skin grafts). A total of 93 patients had toe or = ray=20 amputations, and 254 patients had tarsal-metatarsal amputations. Of 13=20 nonrevascularized patients who did not receive major amputations, 10 had = foot=20 ulcers. Two showed complete healing with a dressing, and eight patients = did not=20 show healing or worsening. All 13 of the nonrevascularized patients = experienced=20 reduced pain that did not disappear, and analgesic medication was = reduced but=20 not discontinued.

Major amputation

A total of 74 (13.4%) patients received major amputations, = 23 in the=20 early period and 51 during follow-up (total incidence per year: 3.72%). =

After PTA, six major amputations were required within 30 = days and 28=20 were performed during follow-up, with an incidence per year of 2.3%. = After BPG,=20 three major amputations were required within 30 days and 21 were = performed=20 during follow-up, with an incidence per year of 5.4%. For patients who = received=20 no revascularization, 14 major amputations were required within 30 days = and two=20 during follow-up, with an incidence per year of 34.3%.

At 30 days, there was no significant difference in the = major=20 amputation rates of PTA and BPG groups (P =3D 0.414), but = during the=20 follow-up, there was a significant difference (P < 0.001). = There=20 were highly significant differences in the major amputation rates of the = two=20 groups (revascularized and not revacularized), both in the early period=20 (=CF=87² =3D 162.6054, P < 0.001) and during = follow-up=20 (=CF=87² =3D 64.3614, P < 0.001).

Multivariate analysis of the variables that were found to = be=20 associated in the univariate analysis confirmed the independent roles of = no=20 revascularization (odds ratio 35.9 [95% CI 12.9=E2=80=9399.7], = P < 0.001),=20 occlusion of each of the crural arteries (8.20 [1.35=E2=80=9349.6], = P =3D 0.022),=20 dialysis (4.7 [1.9=E2=80=9311.7], P =3D 0.001), and wound = infection (2.1=20 [1.3=E2=80=933.6], P =3D 0.004). The analysis shows that a high = TcPO₂=20 value after the treatment has a protective effect (0.8 = [0.74=E2=80=930.87], P=20 < 0.001).

PTA restenosis

After the PTA, a total of 127 clinical restenoses occurred = in 94=20 patients (incidence per year: 6.4%). The restenosis diagnosis was made = in 100=20 case subjects based on the lack of wound healing, with or without pain, = and in=20 27 case subjects based on the reappearance of resting pain without a = foot=20 lesion. The resulting ischemic limb was further revascularized in 81 = patients;=20 72 patients underwent a further PTA and 9 patients underwent a BPG. = These=20 procedures were not practicable in the remaining 13 patients; thus, a = major=20 amputation was required. After the further PTA, 29 patients required = further=20 surgical intervention due to diastasis of the surgical wound.

BPG failure

A total of 36 BPG failures were observed (incidence per = year: 8.8%).=20 Fifteen of these received a PTA or further BPG. Twenty-one patients who = could=20 not sustain further revascularization either by PTA or BPG required = major=20 amputations. In all 21 patients, the major amputation was performed due = to the=20 reappearance of ischemic rest pain with or without ulcers. After = recanalization=20 of the graft, two patients also required a further surgical intervention = due to=20 diastasis of the surgical wound.

Ulcer recurrence

A total of 71 patients were readmitted to our hospital due = to ulcer=20 recurrence without evidence of CLI (incidence per year: 4.3%). The = Wagner grades=20 of these ulcers were 1 for 57 patients, 2 for 11 patients, and 4 for 3 = patients.=20 All the lesions healed without the need for a major amputation; 7 = patients=20 required toe amputations and 64 patients required no minor amputations. = No ulcer=20 recurrences were observed in patients who had PTA restenoses or BPG = failures=20 during follow-up.

CLI incidence and amputation in the contralateral limb

CLI in the contralateral limb was observed in 225 (40.6%) = patients=20 (incidence per year: 14.76%). A major contralateral limb amputation was=20 performed in 15 (6.7%) patients. The amputation rate was significantly = lower in=20 the contralateral limb compared with that in the limb that had the = initial CLI=20 (=CF=87² =3D 7.3, P =3D 0.007).

Survival

A total of 276 (49.8%) patients died, 4 at 30 days and 272 = during=20 follow-up, with an incidence per year of 12.53%. Table = 2=20 reports the causes of death.

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Table 2=20

Causes of death in the followed = population=20 (n =3D 554)

The annual death incidence was not different between = patients who=20 received PTA (n =3D 202; 48.9%) and those who received BPG = (n =3D=20 51, 44.7%; =CF=87² 0.74, P =3D 0.391). The annual = death incidence=20 in patients who received peripheral revascularization (11.9%) was = different from=20 that in patients who did not receive revascularization (52.9%; = =CF=87²=20 53.6, P < 0.001). Figure= 1=20 shows the Kaplan-Meier major amputation and survival estimates for = patients who=20 received PTA, BPG, or no revascularization. Cardiac disease was the = leading=20 cause of death, with an annual incidence rate of 8.1%. Cardiac disease = was due=20 to acute myocardial infarction in 89 (49.7%), pump failure in 72 = (40.0%), and=20 sudden death in 18 (10.1%) patients.

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Figure 1=20

Kaplan-Meier major amputation (A) and = survival (B)=20 estimates in nonrevascularized (NO REV) or revascularized with PTA or = BPG=20 patients.

Multivariate analysis of the variables that were found to = be=20 associated in the univariate analysis confirmed the independent roles of = age=20 (hazard ratio 1.05 for 1 year, P < 0.001, 95% CI = 1.03=E2=80=931.07),=20 unfeasible peripheral revascularization (3.06, P < 0.005,=20 1.40=E2=80=936.70), dialysis (3.00, P < 0.001, = 1.63=E2=80=935.53), and history of=20 cardiac disease (1.37, 1.05=E2=80=931.79). In patients with history of = cardiac disease,=20 impaired ejection fraction was independently associated with death (1.08 = for 1%=20 point, P < 0.001, 1.05=E2=80=931.09).

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CONCLUSIONS

PAD is an underrecognized complication of diabetes (12= ).=20 CLI is an even more underrecognized complication (13= ,14= ).=20 For diabetic patients, the onset of CLI is a dramatic event; the risk of = major=20 amputation and death is considerable. The proper management of CLI could = improve=20 the amputation outcome. Compared with the data reported in the = literature, our=20 series of revascularized patients required decidedly fewer major = amputations in=20 both the early and follow-up periods (15= ).=20 This is most likely due to the ability of our diabetic foot center to = perform=20 both endoluminal and surgical revascularization techniques, thus = providing=20 >95% of the patients with vessel revascularization. The rate of = amputation=20 was consistently lower in patients that received revascularization = compared with=20 patients that could not undergo revascularization (16= ).=20 Moreover, the amputation rate would certainly have been higher if the = latter=20 group of patients had not had such a high mortality rate. Nevertheless, = the=20 center's optimal capacity for revascularization is not enough to reduce = the rate=20 of major amputations. An excellent diagnostic ability and an adequate = ulcer=20 management program postrevascularization are also required (17= ).=20

Recent reports in the literature, and in particular the = recent=20 Cochrane review, have reported that surgical and endoluminal = revascularizations=20 had similar outcomes in terms of mortality and major amputation rates = (18= ,19= ). We=20 also observed similar amputation rates for the two procedures in the = early=20 period, but during the follow-up, the BPG group had a higher amputation = rate=20 than the PTA group. The difference appeared in the Kaplan-Meier curves = at the=20 late follow-up. The only significantly different parameter between the = two=20 groups at admission was the TcPO₂. However, in our protocol, = the BPG=20 was performed only when PTA was impossible; this may have selected = patients with=20 more severe arteriopathy. Nevertheless, the most important message that = emerged=20 from this study regarding the treatment of diabetic patients with CLI = was the=20 enormous difference in the amputation rate between patients that = received and=20 those that did not receive revascularization; this difference was = evident in=20 both the early and the late follow-up periods. This showed that a = successful=20 revascularization was more important than the type of revascularization = used.=20

Readmission to the hospital occurred frequently due to late = failure=20 of revascularization (because of restenosis after PTA or because of = failure of=20 BPG). We found that antiplatelet therapy played an important role in = both PTA=20 restenosis and BPG failure (i.e., we frequently found that patients had = been=20 prescribed insufficient doses of ticlopidine). However, many patients,=20 particularly those who developed restenosis after PTA, received a = further=20 revascularization that enabled them to avoid amputation. These events=20 contributed to the high number of hospitalizations required to minimize = the rate=20 of major amputation. Our data fully agree with other authors who also = found that=20 this population required multiple procedures and admissions (20= ).=20

Incidence of ulcer recurrence was low (=E2=88=BC13% over 6 = years) in this=20 study compared with that reported in the literature (estimated at 50% = over 2=E2=80=935=20 years) (21= ). We=20 believe that this low recurrence was achieved due to the instructions = given to=20 the patients, the relationships established between the caregivers and = the=20 patient, and the protection of therapeutic shoes (22= ).=20

Almost half of our study population developed CLI in the=20 contralateral limb over an =E2=88=BC6-year period. Data from the = literature are rather=20 scarce regarding the fate of the contralateral limb in a diabetic = population=20 with prior CLI in one limb. A few studies published in the early 2000s = reported=20 surveys on the fate of contralateral limbs in patients selected for = major=20 amputations of the initially affected limb, patients with mixed ulcers, = or=20 patients with either neuropathy or ischemia (23= ).=20 Apart from the epidemiological value of our data on the incidence of = CLI, our=20 finding that there was significantly lower frequency of above-the-ankle=20 amputations in contralateral limbs compared with that of initially = affected=20 limbs is predicted to have a high impact on the management of CLI in = diabetic=20 patients. This result shows that early recognition of the pathology and = prompt=20 referral of patients to the diabetic foot center allowed commencement of = treatment under conditions more favorable for combating CLI. Thus, the = prognosis=20 for the contralateral limb was more promising than that for the = initially=20 affected limb.

It is well-known that death associated with cardiac disease = occurs=20 considerably more frequently than amputation in diabetic and nondiabetic = patients affected by PAD. It also is well known that life expectancy is=20 negatively correlated to the severity of the arteriopathy (24= ).=20 Thus, considering the late onset of CLI, it is not surprising that age = had an=20 independent prognostic value on life expectancy in this study (25= ). It=20 may have been possible to increase the survival rate in these patients = if,=20 during the hospitalization for CLI, we had considered improving existing = coronary artery disease (CAD) treatment or evaluating the possibility of = silent=20 ischemia in patients without a history of cardiac disease. In the = future, ad hoc=20 studies will be necessary investigate this question.

Data of this series suggest that aggressive treatment of = CLI in=20 diabetic patients, as practiced in our diabetic foot center, made it = possible to=20 achieve a low rate of major amputation in the initially affected limb = and an=20 even lower rate in the contralateral limb. CAD was the main cause of = death, and=20 in patients with history of CAD, the impaired ejection fraction was the = major=20 independent prognostic factor.

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Acknowledgments

No potential conflicts of interest relevant to this article = were=20 reported.

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Footnotes

The costs of publication of this article were = defrayed in part=20 by the payment of page charges. This article must therefore be hereby = marked=20 =E2=80=9Cadvertisement=E2=80=9D in accordance with 18 U.S.C. Section = 1734 solely to indicate=20 this fact.
- Received July 2, = 2008.
- Accepted February = 3, 2009.=20
Readers may use this article as long as the work is = properly cited,=20 the use is educational and not for profit, and the work is not = altered. See http://creativ= ecommons.org/licenses/by-nc-nd/3.0/=20 for details.
=C2=A9 2009 = by the American=20 Diabetes Association.

Previous=20 Section

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Published=20 online before print February = 17,=20 2009, doi: 10.2337/dc08-1223 Diabetes = Care May 2009 vol. 32 = no. 5 822-827=20

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