JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 9, NO. 24, 2016

2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

ISSN 1936-8798/$36.00
http://dx.doi.org/10.1016/j.jcin.2016.09.039

PERIPHERAL

Endovascular Therapy Versus Bypass

Surgery as First-Line Treatment Strategies
for Critical Limb Ischemia
Results of the Interim Analysis of the CRITISCH Registry
Theodosios Bisdas, MD, PHD,a,b Matthias Borowski, PHD,c Konstantinos Stavroulakis, MD,a
Giovanni Torsello, MD,a,b for the CRITISCH Collaborators

ABSTRACT
OBJECTIVES The most effective rst-line treatment between endovascular therapy and bypass surgery for patients
with critical limb ischemia (CLI) is still not well dened. The primary aim of the interim analysis of CRITISCH (Registry of
First-Line Treatments in Patients With Critical Limb Ischemia) was to compare both treatment options in a prospective
conrmatory manner.
BACKGROUND Only 1 randomized controlled trial between endovascular therapy and bypass surgery has been published yet. Several retrospective studies showed comparable outcomes between the 2 treatment strategies, but in the
majority of them, current endovascular technologies have not been included.
METHODS Between January 2013 and September 2014, 1,200 CLI patients (Rutherford 4 to 6) from 27 vascular centers
were enrolled. The selection of the rst-line treatment was left completely to the discretion of the responsible physician. The
primary composite endpoint was amputation-free survival (AFS), that is, time to major amputation and/or death from any
cause. A pre-specied interim analysis aimed at showing noninferiority of the endovascular therapy versus bypass surgery as
to the hazard ratio (HR) of AFS (noninferiority bound 1.33; interim a 0.0058). Time-to-event analyses of major amputation, death, and the composite endpoint of reintervention and/or above-ankle amputation were also conducted.
RESULTS Endovascular therapy was applied to 642 (54%) and bypass surgery to 284 (24%) patients. Median follow-up
time was 12 months in both groups. One-year AFS was 75% and 72%, respectively. The noninferiority of endovascular
therapy versus bypass surgery for AFS was conrmed (HR: 0.91; upper bound of 1-sided (1  0.0058) condence interval
[CI]: 1.29; p 0.003). An impact of the treatment strategy on time until death (HR: 1.14; 95% CI: 0.80 to 1.63;
p 0.453), major amputation (HR: 0.86; 95% CI:0.56 to 1.30; p 0.463), and reintervention and/or above-ankle
amputation (HR: 0.89; 95% CI: 0.70 to 1.14; p 0.348) was not observed.
CONCLUSIONS The interim analysis conrmed that when physicians are free to individualize therapy to CLI patients,
the endovascular-rst approach achieved a noninferior AFS rate compared with bypass surgery. (Registry of First-Line
Treatments in Patients With Critical Limb Ischemia [CRITISCH]; NCT01877252) (J Am Coll Cardiol Intv 2016;9:255765)
2016 by the American College of Cardiology Foundation.

From the aDepartment of Vascular Surgery, St. Franziskus Hospital GmbH, Muenster, Germany; bDepartment of Vascular Surgery,
University Clinic of Muenster, Muenster, Germany; and the cInstitute of Biostatistics and Clinical Research, University of
Muenster, Muenster, Germany. The German Society of Vascular Surgery and Medicine (Deutsche Gesellschaft fr Gefchirurgie
und Gefmedizin) sponsored this study. The authors have reported that they have no relationships relevant to the contents of
this paper to disclose. Drs. Bisdas and Borowski contributed equally to this work.
Manuscript received August 25, 2016; revised manuscript received September 21, 2016, accepted September 25, 2016.

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Endovascular Versus Bypass Therapy in CLI Patients

ABBREVIATIONS
AND ACRONYMS

he gold standard of treatment be-

METHODS

tween bypass surgery and an endovascular approach in patients with

The study was performed in accordance with the

critical limb ischemia (CLI) is still under

principles in the Declaration of Helsinki. Ethical

debate. Bypass surgery is associated with

approval was obtained from all participating centers

encouraging patency- and amputation-free

before patients were recruited. All patients gave

DCB = drug-coated balloon

survival rate in the long run, especially in

written informed consent. This trial is registered

HR = hazard ratio

cases of autogenous vein conduits (13). On

(NCT01877252).

RCT = randomized controlled

the other hand, recovery following endovas-

A detailed description of the study design has been

trial

cular therapy is faster than after bypass sur-

previously published (8,9). Briey, the CRITISCH

SFA = supercial femoral

gery, and the minimally invasive nature of

registry is a prospective, multicenter registry assess-

the

additional

ing the current practice of all available treatments

wound or anesthesia-associated morbidity

strategies in all-comers CLI patients treated in 27

(up to 20%) (14). The BASIL (Bypass Versus

vascular centers of excellence (Online Appendix).

AFS = amputation-free survival

CI = condence interval
CLI = critical limb ischemia

artery

TASC = Trans-Atlantic
Inter-Society Consensus

procedure

prevents

any

Angioplasty for Severe Ischemia of the Leg) trial,

Two criteria were used for the denition of a center of

which still remains the only published randomized

excellence: 1) implemented CLI program with use of

controlled trial (RCT) in this eld, showed compara-

both endovascular and surgical techniques; and/or 2)

ble outcomes between the strategies (4), but favored

selection of the treatment strategy after a vascular

bypass surgery for patients with a life expectancy

conference

>2 years (5).

(vascular

between

the

responsible

disciplines

surgeons/cardiologists/radiologists).

At

least 1 operator should be board certied (i.e.,

SEE PAGE 2566

specialist) for the respective discipline. No further

Meanwhile, an evolution in the endovascular eld

selection criteria for the interventionalist were used.

was undertaken, and several RCTs conrmed the su-

The inclusion criterion of this study was the

periority of the current technologies to plain balloon

presence of new onset CLI. CLI was dened as an

angioplasty, which has been investigated in the BASIL

ankle-brachial index <0.40 or ischemic rest pain, or

trial (6). However, patients with CLI were the mi-

both, with or without tissue loss in the presence

nority, if not an exclusion criterion, in those RCTs,

of peripheral arterial disease (Rutherford classes 4

and evidence concerning the effectiveness of these

to 6/Fontaine III to IV) lasting >2 weeks. In case

modalities in this challenging cohort is still missing.

of a noncalculable index, ankle pressure or trans-

Moreover, there is a paucity of comparative data be-

cutaneous oxygen pressure was measured, as estab-

tween the new technologies and bypass surgery (7). In

lished at each center. Only 1 limb per patient was

this context, the results of the BASIL 2/3 and the

included. The modied PREVENT III (Edifoligide for

BEST-CLI (Best Endovascular Versus Best Surgical

the Prevention of Vein Graft Failure in Lower

Therapy in Patients With Critical Limb Ischemia)

Extremity Bypass SurgeryPhase III Trial) score was

trials will surely provide strong evidence regarding

used to address the frailty of the patients, due to

this debate. However, due to delays and difculties

its proven predictive role for short- and long-term

in recruitment, the rst results are anticipated

outcomes after infrainguinal surgical revasculariza-

after 2019.

tion (10) or endovascular therapy (11). The study

To inform the published reports as to the afore-

excluded patients with acute limb ischemia (embolic

mentioned issues, we conducted a prospective,

or thrombotic), isolated aortoiliac interventions,

multicenter registry of all rst-line treatment stra-

vascular trauma of the index leg, known clotting

tegies in patients with CLI (CRITISCH [Registry of

disorders, and non-atherosclerotic vascular disease

First-Line Treatments in Patients With Critical Limb

(e.g., vasculitis) (8).

Ischemia]) (8). All available endovascular techniques

The registry was validated via an audit at partici-

at the time of patients recruitment were included

pating centers to monitor how accurately all patients

and evaluated. In the framework of our pre-planned

and procedures were documented. The recruitment

interim analysis, we compared the endovascular

of the target cohort started in January 2013 and was

approach to bypass surgery as to amputation-free

completed in September 2014. The selected treatment

survival in a prospective conrmatory manner. Our

strategy was left completely at the discretion of the

initial

endovascular

treating physician following the principle of best

approach is not inferior to conventional bypass

medical practice; in case of CLI, where there are grey

surgery.

zones of medical practice for which evidence is

hypothesis

was

that

an

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Endovascular Versus Bypass Therapy in CLI Patients

conicting or not existing, the case decisions had to

endovascular treatment versus bypass surgery by the

rely on health professional experience, judgment,

(adjusted) hazard ratio (HR) of AFS. In order to

and the choice of patients (12).

conrm the noninferiority of endovascular treatment

There was no limitation concerning the selected

versus bypass surgery as to this HR, the 1-sided Wald

treatment option. The different rst-line treatment

test was applied. The noninferiority of endovascular

strategies were classied into 5 groups. Group I

treatment versus bypass surgery had been dened by

included patients undergoing all types of endovas-

a HR <1.33. In order to maintain a global signicance

cular repair. Endovascular repair was considered any

level a 2.5%, the local level a 0.58% was pre-

percutaneous endovascular attempt for guidewire

specied to be used in the interim analysis. The

traversal of lesions. In 6 cases, a lesion could not be

interim analysis was also carried out pursuing a kind

crossed. In these cases, the endovascular approach

of per-protocol approach. In this per-protocol anal-

remained the rst-line treatment, and any further

ysis, 6 patients from group I were removed from

surgical revascularization was considered a reinter-

analysis because the complete lesion could not be

vention. Group II consisted of patients undergoing

crossed, and therefore, surgical revascularization was

primarily bypass surgery with all type of conduits. We

applied. Further exploratory analyses were conduct-

included all types of conduits in order to demonstrate

ed in the course of the interim analysis, using com-

real-world practice as to this issue. Group III included

mon descriptive (median, quantiles, interquartile

patients undergoing common/deep femoral artery

range

patchplasty, with or without a concomitant distal

Kaplan-Meier

endovascular intervention. For this reason, these

Whitney test, Fisher test, chi-square test, log-rank

patients were not analyzed together with those of

test, Wald test, condence intervals [CIs]) statistical

group II. Finally, group IV included patients treated

methods. Statistical computations were performed

conservatively, whereas group V subjects underwent

using R version 3.1.2 (R Foundation for Statistical

primary major amputation.

Computing, Vienna, Austria).

ENDPOINTS. The primary composite endpoint of the

RESULTS

[IQR], absolute and relative frequencies,

estimates)

and

inferential

(Mann-

CRITISCH registry was amputation-free survival

(AFS), that is, time until major amputation of the in-

Endovascular treatment (group I) was applied to 642

dex limb and/or death from any cause. A major

(53%) and bypass surgery (group II) to 284 (24%;

amputation was considered any above-ankle amputation. Secondary endpoints analyzed in this paper
were time until death, time until amputation at the

T A B L E 1 Demographics, Symptomatology, and Anatomic Characteristics in Each Group

Group I:
Endovascular

index limb, as well as time until major amputation

and/or any reintervention at the index limb.
STUDY

DESIGN

AND

STATISTICAL

Age, yrs

ANALYSIS. A

Modied PREVENT III risk score

75 (6883)
5 (28)

Group II: Bypass

Surgery

73 (6579)
4 (26)

p Value

<0.001
<0.001

exible adaptive-sequential study design with 1

Females

237 (37)

92 (32)

interim analysis of the primary endpoint AFS was

Males

405 (63)

192 (68)

Diabetes

310 (48)

136 (48)

0.943

eGFR <60 ml/min/m2

316 (49)

99 (35)

<0.001

established. The statistical analysis was pre-specied

before the recruitment started and was concretized in

Dialysis-dependent

64 (10)

13 (5)

0.006

93 (14)

40 (14)

0.919

298 (46)

118 (42)

0.174

25 (4)

17 (6)

0.172

Statin at discharge

359 (56)

176 (62)

TASC A or B

218 (34)

19 (7)

TASC C or D or not applicable

423 (66)

265 (93)

1 or more runoff vessels

469 (73)

253 (89)

141 (22)

72 (25)

a statistical analysis plan before the interim analysis

Obesity

was conducted. Hence, the results of the primary ef-

Angina/coronary heart disease

cacy analysis provide conrmatory evidence. Power

Previous myocardial infarction <6 months

calculations delivered a target cohort of 1,200 patients to be assessed for eligibility. The interim analysis was planned to be carried out after 250 events
occurred. Because randomization of the treatment

0.206

Rutherford 4

strategy was not feasible, we planned to establish a

Rutherford 5

375 (58)

140 (49)

multivariable Cox regression model of AFS including

Rutherford 6

126 (20)

72 (25)

the treatment strategy (endovascular treatment vs.

PVI*

251 (39)

139 (49)

0.097
<0.001
<0.001
0.031
0.006

bypass surgery) and further prognostic factors as

covariates. The strategy of model building and the
possible

prognostic

covariates

had

been

pre-

specied. By creating the multivariate Cox model,

we were able to quantify the treatment effect of

Values are median (interquartile range) or n (%). *Only patients with new onset of CLI at the time of presentation
and not these with ongoing CLI symptoms after the last PVI at the index limb were included.
CLI critical limb ischemia; eGFR estimated glomerular ltration rate; IQR interquartile range; PREVENT
III Edifoligide for the Prevention of Vein Graft Failure in Lower Extremity Bypass SurgeryPhase III Trial;
PVI previous vascular intervention; TASC Trans-Atlantic Inter-Society Consensus.

Bisdas et al.

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Endovascular Versus Bypass Therapy in CLI Patients

p < 0.001) patients. Table 1 summarizes the demo-

T A B L E 2 Endovascular Devices and Bypass Conduits

Femoral
Vessels
(n 347)

Popliteal
Vessels
(n 272)

graphics and comorbidities of the patients, the

Tibial
Vessels
(n 368)

Previous
Bypass
(n 26)

Balloon angioplasty

125 (36)

104 (38)

259 (70)

8 (31)

Bare-metal stent

141 (41)

90 (33)

24 (7)

3 (12)

Drug-coated balloon

63 (18)

53 (20)

36 (10)

2 (8)

Other*

the lesions in each group. Table 2 provides an overview of the endovascular devices, as well as the type

Endovascular therapy (n 642)

Drug-eluting stent

Rutherford stages, and the anatomic characteristics of

6 (2)

2 (1)

12 (3)

2 (8)

38 (11)

32 (12)

22 (6)

12 (46)

Bypass surgery (n 284)

of bypass conduits used.

Median length of the in-hospital stay was 7 days
(interquartile range [IQR]: 3 to 14 days) in group I and
15 days (IQR: 11 to 26 days) in group II (p < 0.001). In
group I, 563 patients (88%) were discharged home
compared with 216 patients (76%) in group 2 (p <

Autologous vein graft

159 (56)

Prosthetic material

125 (44)

0.001). In-hospital mortality amounted to 1% (n 7)

Polyester

32 (26)

in group I and 3% (n 8) in group II (p 0.085),

Polytetrauorethylene

71 (57)

whereas the major amputation rate was 3% (n 20) in

Other

22 (17)

group I and 4% (n 10) in group II (p 0.841).

Distal anastomosis
75 (26)

PRIMARY ENDPOINT. The median follow-up was

Autologous vein graft

27 (36)

approximately 1 year in both groups (group I 373 days,

Prosthetic material

48 (64)

group II 365 days), and the AFS rate at 1 year was 75%

80 (28)

in group I and 72% in group II. The Kaplan-Meier plot

Autologous vein graft

46 (58)

Prosthetic material

34 (42)

(Figure 1) and log-rank test (p 0.994) did not indi-

Above-knee

Below-knee

Crural/pedal

129 (46)

Autologous vein graft

Prosthetic material

cate a difference in AFS between the groups.

86 (67)

The multivariate Cox regression model of AFS

43 (33)

(Table 3) considered all variables listed in Table 1 as

possible confounders of the treatment effect. After

Values are n (%). *Atherectomy/thrombectomy devices, scoring/cutting-balloon catheter,

stent-grafts.

adjustment for several inuential confounders, the

model delivers a HR of AFS (comparing endovascular
treatment vs. bypass surgery) of 0.91 with an estimated 2-sided 95% CI of 0.70 to 1.19. (Note that we
did not nd any systematic structures in the
Schoenfeld residuals of each covariate over time,
which is why we conclude that the assumption of
proportional hazards is justiable.)

F I G U R E 1 Relation Between Treatment Strategy and AFS

The 1-sided (1  a )-CI of the HR was derived

from this multivariate Cox model (Wald test) with

Amputation-free survival

a 0.0058 being the local signicance level of the

100

Endovascular
Bypass

interim analysis. Because the p value was p 0.0029 <

a 0.0058 or, equivalently, because the upper bound

of the (1  0.0058)-CI was 1.29 and, thus, smaller than

80

the pre-specied noninferiority bound of the HR of

1.33, we were able to conrm signicant noninferiority

60
%

of endovascular treatment versus bypass surgery as to

the AFS at a 2.5% level of signicance. In a kind of

40

per-protocol analysis, 6 patients of group I were

excluded from the full analysis set because the rstn at risk:

20

458

337

227

75

line endovascular approach failed and a bypass sur-

195

129

73

31

gery was applied instead. This per-protocol analysis

0
0

12

18

Logrank-test: p=0.994

delivered similar results with an upper bound of the

24

(1  0.0058)-CI of 1.30 and a p value of 0.003.

30

Months

SECONDARY ENDPOINTS. Because AFS is a compos-

ite endpoint, we also investigated the inuence of the

The rates were estimated by the Kaplan-Meier method and were only drawn if the standard

treatment strategy on the freedom from amputation

error was <10%. AFS amputation-free survival.

and the overall survival by means of Kaplan-Meier

estimation (Figures 2 and 3). At 12 months, freedom

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DECEMBER 26, 2016:255765

time until major amputation and/or reintervention.

T A B L E 3 Amputation-Free Survival

However, age (HR: 0.99), no run-off vessels (HR: 1.56),

HR

95% CI

0.91

(0.701.19)

0.492

1.12

(1.031.20)

0.004

Diabetes vs. no diabetes

1.25

(0.981.59)

0.074

eGFR <60 vs. eGFR $60 ml/min

1.44

(1.091.89)

0.010

Endovascular vs. bypass

p Value

Age, yrs (x vs. x  1)

Modied PREVENT III risk score

previous vascular intervention (HR: 1.70), and no

statin administration during surveillance (HR: 1.33)
were identied as risk factors for this endpoint.

Male vs. female

DISCUSSION

Obesity vs. no obesity

In this study, we compared the outcomes between

Angina vs. no angina

bypass surgery and an endovascular approach in

PMI vs. no PMI

patients with CLI in the framework of the pre-planned

TASC C/D/not applicable vs. A/B

interim analysis. Adjustment for several confounders

0 vs. 1 or more run-off vessels

by means of multivariate Cox regressions was neces-

Rutherford 5 vs. Rutherford 4

0.80

(0.541.18)

0.253

Rutherford 6 vs. Rutherford 4

1.37

(0.902.08)

0.147

1.24

(0.981.58)

0.078

PVI vs. no PVI

No statin vs. statin

2561

Endovascular Versus Bypass Therapy in CLI Patients

sary, because noticeable differences between the

groups were observed (Table 1). However, these
differences could highlight a number of selection
criteria of the physicians regarding each treatment

Hazard ratios (HRs) of AFS with 95% condence intervals (CIs) were obtained by
multivariate Cox regression; to prevent overtting, model building was carried out
by all-subset variable selection based on the Akaike Information Criterion, so not
all variables were included into the nal model.
PMI previous myocardial infarction; other abbreviations as in Table 1.

strategy. Patients receiving endovascular treatment

were older and frailer (higher PREVENT III score),
they more frequently had chronic kidney disease and
usually presented with ischemic lesions of the digits
(Rutherford class 5). The angiography revealed a
poorer run-off status, despite the moderate angio-

from amputation was 90% in group I and 85% in group

graphic lesions (TASC [Trans-Atlantic Inter-Society

II, and overall survival amounted to 81% in group I and

Consensus] II A/B). As to this issue, TASC II classi-

84% in group II. The log-rank tests indicated that

cation is mainly a treatment suggestion and less an

there might be a difference between the groups as to

angiographic description of the hemodynamic impact

freedom from amputation (p 0.077) and overall

of the lesion. On the other hand, bypass surgery was

survival (p 0.036). However, after adjustment for

applied more commonly in patients having already 1

relevant confounders by multivariate Cox regression

or

more

previous

vascular

interventions.

This

analysis (Table 4), these differences could not be

observed anymore, neither for time to amputation
(HR: 0.86; 95% CI: 0.56 to 1.30; p 0.463) nor for
survival (HR: 1.14; 95% CI: 0.80 to 1.63; p 0.453).

F I G U R E 2 Relation Between Treatment Strategy and Freedom From Amputation

The hazard of AFS is increased by an increase of the

Freedom from amputation

modied PREVENT III score (HR: 1.12), by the presence

100

of chronic kidney disease (HR: 1.44) or diabetes mel-

Endovascular
Bypass

litus (HR: 1.25), and the absence of statin use during

follow-up (HR: 1.24) (Table 4). Considering limb loss,

80

again chronic kidney disease (HR: 1.62), Rutherford

(HR: 2.27), and previous vascular

in-

tervention(s) (HR: 1.95) were identied as risk factors.

Regarding overall survival, an increased modied

60
%

stage 6

40

PREVENT III score (HR: 1.15) and chronic kidney disease (HR:1 .58) were linked with an increased hazard.
An inuence of the treatment strategy on the

n at risk:

20

time until major amputation and/or reintervention

could not be observed by Kaplan-Meier estimations
(Figure 4) and log-rank test (p 0.381). The rate of

458

337

227

75

195

129

73

31

Logrank-test: p=0.077

0
0

event-free survival at 12 months was 65% in group I

12

18

24

30

Months

and 62% in group II at 12 months. The numbers of

events were 212 (33%) in group I and 98 (35%) in group

The rates were estimated by the Kaplan-Meier method and were only drawn if the standard

II. Multivariate Cox models (Table 5) also delivered no

error was <10%.

indication that the treatment strategy inuences the

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Endovascular Versus Bypass Therapy in CLI Patients

benet from revascularization compared to medical

F I G U R E 3 Relation Between Treatment Strategy and Overall Survival

therapy alone at all stages of renal impairment.

However, the best revascularization method in those

Overall survival

patients remains unknown und requires further

100

Endovascular
Bypass

investigation, considering that 44% of the total

cohort in our registry suffered from chronic kidney
disease (7,15). Our multivariate Cox regression ana-

80

lyses revealed chronic kidney disease as a risk factor

for the composite endpoint, limb loss, and overall

60
%

mortality. Of note, a separate analysis of the impact of

dialysis on the primary endpoint was not reasonable

40

due to the small number of dialysis-dependent patients in both groups (Table 1).
n at risk:

20

480

351

237

79

Our initial hypothesis, that the endovascular repair

209

146

82

33

was not inferior to bypass surgery could be conrmed

0
0

12

18

Logrank-test: p=0.036

in the framework of the planned interim analysis at a

24

2.5% level of signicance. The AFS amounted to 75%

30

Months

in group I and 72% in group II at 1 year. Analyzing

separately overall survival and freedom from ampu-

The rates were estimated by the Kaplan-Meier method and were only drawn if the standard

tation, both cohorts showed comparable outcomes

(81% vs. 84% and 90% vs. 85%, respectively) as well.

error was <10%.

The BASIL trial showed also comparable effectiveness

between angioplasty and bypass surgery although
patients with life expectancy >2 years would benet
conrms the results of previous studies (13), which

more from bypass surgery (4,5). However, the study

identied similar empiric selection criteria between

design has been criticized, and the inclusion of only

the strategies and proves that decision making is

angioplasty cases in the endovascular arm makes the

still in accordance to Trans-Atlantic Inter-Society

results of this trial less representative of the current

Consensus Document on Management of Peripheral

practice. Our study indicates that for patients who

Arterial Disease II guidelines (14); patients undergo-

do not meet the criteria of the RCTs, the bias intro-

ing an endovascular approach are skewed to more

duced by allowing skilled physicians to practice

severe clinical presentation and less severe anatomic

medicine and to come to treatment decisions does not

lesions. Nonetheless, endovascular repair led to

compromise patient outcomes.

shorter median length of in-hospital stay and higher

rates of ambulatory patients post-discharge.

Several retrospective studies have also compared

endovascular therapy and bypass surgery in CLI pa-

It is interesting that physicians choose to apply

tients, and a meta-analysis of them (January 1995 to

more frequently the endovascular therapy, despite

August 2012) showed no difference in amputation-free

use of nephrotoxic contrast agent, as primary

survival and all-cause mortality (20). Abu Dabrh et al.

approach in patients with chronic kidney disease.

(21) performed a systematic review of all comparative

Chronic kidney disease was a noticeable contributor

studies through October 2014 and again suggested that

to in-hospital mortality in our registry (8,15), and this

endovascular approaches and bypass surgery may

was also conrmed by Willenberg et al. (16). Once

have a similar effect on mortality and major amputa-

advanced kidney disease is present, it may contribute

tion. As expected, a common nding of both meta-

to the progression of systemic endothelial dysfunc-

analyses was that the quality of evidence was low

tion more than traditional cardiovascular risk factors

due to imprecision and heterogeneity between the

do (17). More interestingly, a recent study showed

studies. To our best knowledge, the included studies

that statins have no protective effect against cardio-

in both meta-analyses used either plain balloon an-

vascular morbidity in patients with end-stage renal

gioplasty or bare-metal stenting (19,20).

disease (18). However, little is known as to the

In our study, different technologies of the endo-

effectiveness of different treatment strategies in pa-

vascular armamentarium (Table 2) were assessed. In

tients with chronic kidney disease and especially in

the supercial femoral artery (SFA), the majority of

those with end-stage renal disease, because these

the patients were treated with bare-metal stents

patients are excluded in the majority of RCTs. Ort-

(41%). Despite the fact that few data as to the effec-

mann et al. (19) showed that patients with CLI will

tiveness of drug-coated balloons (DCBs) in the SFA in

Bisdas et al.

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DECEMBER 26, 2016:255765

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Endovascular Versus Bypass Therapy in CLI Patients

T A B L E 4 AF Time and OS

Multivariate Cox Model for AF

Multivariate Cox Model for OS

HR

95% CI

p Value

HR

95% CI

p Value

Endovascular vs. bypass

0.86

(0.561.30)

0.463

1.14

(0.801.63)

0.453

Age, yrs

0.97

(0.950.99)

0.001
1.15

(1.071.24)

<0.001

1.41

(0.902.21)

0.136

1.62

(1.082.43)

0.021

1.58

(1.142.19)

0.006

1.60

(0.912.82)

0.102

1.29

(0.931.77)

0.125

1.27

(0.961.70)

0.096

Modied PREVENT III risk score

Male vs. female
Diabetes vs. no diabetes
eGFR <60 vs. eGFR $60 ml/min
Obesity vs. no obesity
Angina vs. no angina
PMI vs. no PMI
TASC C/D/not applicable vs. A/B
0 vs. 1 or more run-off vessels
Rutherford 5 vs. Rutherford 4

0.82

(0.481.40)

0.470

Rutherford 6 vs. Rutherford 4

2.27

(1.333.88)

0.003

PVI vs. No PVI

1.95

(1.302.93)

0.001

No statin vs. statin

HRs of amputation-free time (AF) and overall survival (OS) with 95% CI were obtained by multivariate Cox models.
Abbreviations as in Tables 1 and 3.

CLI patients existed at the time of recruitment, 18% of

devices and atherectomy in the femoropopliteal le-

the patients in our study received DCB therapy in the

sions are mainly the lack of evidence as to the effec-

SFA. Similar rates of DCB therapy were applied also

tiveness of these devices in CLI patients, the missing

in the popliteal artery (19%), where again, primary

reimbursement at the time of recruitment, and the

stenting was the leading therapy (33%). Likely, the

high procedural costs, especially in regard to drug-

length or severity of the complex femoropopliteal

eluting stents and atherectomy (6).

lesions in CLI patients might lead to subintimal

recanalization requiring primary stenting. In this
context, we are not able to provide more data about
the exact location (p1 to p3 segment) of the stent as
well, as its type (e.g., interwoven nitinol stent).
Finally, as to the infrapopliteal vessels, the majority

F I G U R E 4 Relation Between Treatment Strategy and Freedom From

Major Amputation and/or Any Reintervention at the Index Limb

of the patients received plain balloon angioplasty

Freedom from major amputation and/or any reintervention

(70%), and only 10% of patients underwent DCB an100

gioplasty, probably due to the results of the InPact

Endovascular
Bypass

DEEP trial (Study of IN.PACT Amphirion Drug

Eluting Balloon vs. Standard PTA for the Treatment of

80

Below the Knee Critical Limb Ischemia) (22). Despite

the encouraging 12-month outcomes of the XCELL
the Xpert(TM) Stent in Treating Below-the-knee Le-

60
%

trial (Study to Evaluate the Safety & Performance of

40

sions in Patients Undergoing Percutaneous Intervention for Chronic CLI) as to primary infrapopliteal
nitinol stenting, 7% of the patients received this type

n at risk:

20

of therapy (23). Important to mention is also that few

physicians choose primary stenting with a drugeluting stent in the SFA (2%) or popliteal artery

378

249

155

50

156

98

53

23

Logrank-test: p=0.381

0
0

(0.7%). By contrast, 3.3% of patients received drug-

12

18

24

30

Months

eluting stents in the tibial vessels and 8% of patients in the distal anastomosis after previous bypass.

The rates were estimated by the Kaplan-Meier method and were only drawn if the standard

Possible explanations for the low implementation

error was <10%.

rate of the new technologies, namely, drug-coated

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Bisdas et al.

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DECEMBER 26, 2016:255765

Endovascular Versus Bypass Therapy in CLI Patients

groups, as reported elsewhere (8). Finally, a cost

T A B L E 5 Major Amputation and/or Reintervention-Free Time

analysis was not done as part of this registry.

Multivariate Cox Model for

MALE-Free Time
HR

CONCLUSIONS

95% CI

p Value

Endovascular vs. bypass

0.89

0.701.14

0.348

Age, yrs

0.99

0.981.00

0.012

0 vs. 1 or more run-off vessels

1.56

1.212.00

0.001

PVI vs. no PVI

1.70

1.352.12

<0.001

No statin vs. statin

1.33

1.061.66

0.014

Regarding the primary endpoint, the interim analysis

of the CRITISCH registry conrmed signicant noninferiority of the current endovascular approach in
comparison to bypass surgery as rst-line treatment
strategy. This study highlights that when physi-

HR of major amputation and/or reintervention-free time with 95% CI were

obtained by multivariate Cox models.
MALE major adverse limb event(s); other abbreviations as in Tables 1 and 3.

cians are free to individualize therapy for their CLI

patients, they achieved encouraging outcomes with
both therapies. Despite the fact that sicker and
higher risk patients were included in the endovas-

STUDY LIMITATIONS. We are not able to report on

the exact selection criteria for each patient separately. These can be only extrapolated by comparing
the baseline characteristics between the groups. The
registry aimed at including consecutive patients
based on the bedside clinical examination by the
treating physician. The same person assessed and
reported the angiographic and ultrasound ndings as
well as whether an endpoint was met. We chose AFS
as primary endpoint to be in accordance with previous studies as to CLI; however, this can be criticized
considering that a major adverse limb event, meanwhile, has been described as a superior outcome (24).
We are not able to provide a number of details as to
the type of previous interventions, the exact endo-

cular group, a low early mortality rate as well as a

statistically
compared

noticeable
with

bypass

shorter
surgery

in-hospital
were

stay

observed.

Because chronic kidney disease was the most striking

risk factor for limb loss and death, this cohort
requires further investigation as to the most effective
treatment.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Theodosios Bisdas, Department of Vascular Surgery,

St. Franziskus Hospital GmbH, Hohenzollernring 72,
Muenster D-48147, Germany. E-mail: th.bisdas@
gmail.com.
PERSPECTIVES

vascular products and their manufacturers, the primary or secondary patency of the treated lesions or

WHAT IS KNOWN? The gold standard of treat-

implanted bypass grafts, the time to wound healing,

ment between the endovascular-rst and the

and the exact reason of death. In our study, we could

bypass-rst approaches in patients with CLI re-

not assess whether the quality or availability of the

mains under debate with only 1 randomized

vein graft conduit was the reason to choose a pros-

controlled trial published more than a decade ago.

thetic bypass graft or an endovascular approach as

Decision making is based mostly on local expertise,

the

rst-line

treatment

strategy

(25).

Because

randomization was not feasible, a multivariate Cox

regression model was established in order to prevent
biased results. Concrete instructions of model building were dened before the interim analysis was
performed. Hence, we were able to show signicant
noninferiority

of

endovascular-rst

approach

in

comparison to bypass surgery as to the HR of AFS in a

conrmatory manner. In this context, we performed
a regression-adjusted analysis and not a matched pair
analysis, due to the arguments given by Klein et al.
(26). In particular, we wanted to use all the patient
information, including also those patients for whom
we could not nd a match. Any comparison to the
outcomes of the other rst-line treatments (groups III
to V) was not reasonable due to the high heterogeneity of the cohorts and the small sizes of the other

and little is known about the outcomes of

physician-directed CLI therapy.
WHAT IS NEW? Our study shows in a conrmatory
manner that for patients who do not meet the criteria
of the randomized controlled trials, the bias introduced by allowing skilled physicians to individualize
their therapy and make treatment decisions does not
compromise patient outcomes for either endovascular
therapy and bypass surgery.
WHAT IS NEXT? More evidence is needed to
improve our knowledge about the treatment of choice
in CLI patients with renal impairment, considering that
this was the most striking risk factor for both amputation and death.

Bisdas et al.

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 9, NO. 24, 2016

DECEMBER 26, 2016:255765

Endovascular Versus Bypass Therapy in CLI Patients

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KEY WORDS amputation-free survival,

bypass surgery, critical limb ischemia,
endovascular therapy

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of amputation-free survivalin patients undergoing infrainguinal autogenous vein bypass for

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A PP END IX For a list of the CRITISCH

collaborators, please see the online version of
this article.

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