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\begin{document}

\title{The Role of Conservative Management in Treatment of Critical Limb
Ischemia}



\author[1]{Sara Mohamed}%
\author[1]{Deirdre C  Mc Dermott}%
\author[1]{Khalid Ahmed}%
\author[1]{Veronica McInerney}%
\author[1]{Linda Howard}%
\author[2]{Muhammad Tubassam}%
\author[1]{Timothy O'Brien}%
\author[1]{STEWART WALSH}%
\affil[1]{National University of Ireland Galway}%
\affil[2]{Galway University Hospitals}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Revascularization has been considered the gold standard
treatment for critical limb ischemia (CLI). Due to the high morbidity
and mortality associated with intervention, evidence has emerged
recently supporting the suitability of conservative management as a
primary option to achieve amputation-free survival (AFS) in CLI patients
even when revascularization is technically feasible. Methods: A
prospective database of CLI patients was developed during pre-screening
of patients for a phase 1 stem cell therapy clinical trial. The overall
survival (OS) and AFS rates for patients treated with revascularization
were compared to those treated conservatively. Statistical significance
was set as p value \textless{} 0.05. OS and AFS for the two groups were
estimated by Kaplan-Meier survival curves. Results: Patients in the
conservative group were more likely to have Rutherford Class 5 and be
diabetic while they were less likely to be active smokers or have
hyperlipidemia (Table 1). There were no significant differences between
the two groups in mortality, amputation, overall AFS or one-year AFS
rates. Kaplan-Meier cumulative OS and AFS over the 3 years follow-up
period of the study demonstrated significant differences between the
conservative and revascularization groups (Log Rank: 0.031 \& 0.045;
respectively). This statistical significance was not detected when
one-year AFS was evaluated (Log Rank 0.096). Conclusion: Conservative
management can be a suitable management option to achieve one-year AFS
for some CLI patients. Further studies are needed to identify robust
clinical criteria for identifying patients who will benefit from
conservative management.%
\end{abstract}%



\sloppy


\textbf{The Role of Conservative Management in Treatment of Critical
Limb Ischemia}

\textbf{KEYWORDS:} Critical Limb Ischemia, Revascularization,
Conservative Management, Amputation-free Survival

\textbf{ABSTRACT}

\textbf{Background:} Revascularization has been considered the gold
standard treatment for critical limb ischemia (CLI). Due to the high
morbidity and mortality associated with intervention, evidence has
emerged recently supporting the suitability of conservative management
as a primary option to achieve amputation-free survival (AFS) in CLI
patients even when revascularization is technically feasible.

\textbf{Methods:} A prospective database of CLI patients was developed
during pre-screening of patients for a phase 1 stem cell therapy
clinical trial. The overall survival (OS) and AFS rates for patients
treated with revascularization were compared to those treated
conservatively. Statistical significance was set as \emph{p} value
\textless{} 0.05. OS and AFS for the two groups were estimated by
Kaplan-Meier survival curves.

\textbf{Results:} Patients in the conservative group were more likely to
have Rutherford Class 5 and be diabetic while they were less likely to
be active smokers or have hyperlipidemia (Table 1). There were no
significant differences between the two groups in mortality, amputation,
overall AFS or one-year AFS rates. Kaplan-Meier cumulative OS and AFS
over the 3 years follow-up period of the study demonstrated significant
differences between the conservative and revascularization groups (Log
Rank: 0.031 \& 0.045; respectively). This statistical significance was
not detected when one-year AFS was evaluated (Log Rank 0.096).

\textbf{Conclusion:} Conservative management can be a suitable
management option to achieve one-year AFS for some CLI patients. Further
studies are needed to identify robust clinical criteria for identifying
patients who will benefit from conservative management.

\textbf{What is already known about this topic?}

Revascularization is the recommended management option for critical limb
ischemia (CLI). Amputation-free survival (AFS) is a reliable outcome
measurement tool to assess effectiveness of CLI treatment.

\textbf{What does this article add?}

This article provides evidence of the comparability of conservative
management to revascularization in terms of risk of mortality and/or
amputation in the studied cohort.

\textbf{Introduction:}

Critical limb ischemia (CLI) is the most severe stage of peripheral
vascular disease (PVD), affecting 3-10\% of the population {[}1{]}.
Clinically, patients present with rest pain and/or tissue loss (ulcers
or gangrene). Revascularization has been considered the gold standard
treatment for CLI, based on the guidelines of the Inter-Society
Consensus for the Management of Peripheral Arterial Disease (TASC II)
{[}2{]}. However, the short term risk of amputation and/or death after
revascularization remains high {[}3{]}. A multicentre clinical trial
reported only 35\% amputation-free survival rate at 5 years after either
surgical bypass or endovascular angioplasty {[}4{]}. There is also a
considerable morbidity after revascularization related to wound
infection or grafts occlusion requiring re-intervention. Therefore,
careful patient assessment is crucial to determine the risk/benefit
ratio prior to intervention.

Revascularization cannot be achieved in 25 -- 40\% of patients {[}2{]},
due to medical comorbidities or anatomically diffuse disease. These
``no-option'' CLI patients are at high risk for major amputation and/or
death. Nevertheless, some of these patients improve significantly on
conservative management with best medical therapy and optimal wound
care. A retrospective cohort study of 144 patients reported no
significant improvement in amputation-free survival (AFS) of invasively
treated patients, concluding that ``not all CLI patients require
revascularization'' {[}5{]}. A systematic review including 11 clinical
trials revealed significant improvement in AFS for no-option CLI
patients {[}6{]}, indicating the important role of conservative
management as a definite treatment for CLI.

In this study, we compare the overall survival (OS) and AFS rates for
patients treated with revascularization versus conservative management,
to determine suitability of the latter as a main first line treatment
for CLI even when revascularization is technically feasible.

\textbf{Methods:}

A prospective database of CLI patients was established during
pre-screening of CLI patients for phase 1b stem cells therapy clinical
trial {[}7{]}. CLI patients, attending the vascular service at a
tertiary university hospital in the West of Ireland between April 2015
and April 2018, were included in the study. CLI was defined clinical
presentation with rest pain (Rutherford class 4) and/or tissue loss
(Rutherford class 5 and 6) for at least 2 weeks with proven underlying
vascular occlusive disease. Patients presenting with acute limb ischemia
were excluded from the study.

The following demographic data and medical comorbidities were recorded:
age, gender, smoking status, diabetes, hypertension, hyperlipidaemia,
cardiac disease (including ischemic heart disease and heart failure),
cerebrovascular disease (including transient ischemic attack and
stroke), chronic obstructive pulmonary disease (COPD)/ asthma, and
chronic kidney disease.

Patients were divided to two groups: ``Revascularization group'' and
``Conservative management group''. The revascularization group included
all patients who had either surgical or endovascular intervention as the
primary treatment for CLI. The conservative management group included
patients classified as ``no-option'' due to unfavourable anatomy for
intervention or medical comorbidities. This group also included patients
for whom revascularization was recommended but who improved on best
medical therapy and modification of risk factors prior to intervention.

The end point of the study was defined as: the date of last follow-up,
or date of death, or date of major amputation (below or above the knee).
The study outcomes were overall survival and amputation-free survival.

The statistical analysis was performed using StatsDirect 3 (~Llumina
Press 2010). The descriptive data was expressed as mean and standard
deviation and compared using student t test. Fisher extract test was
used for analysis of categorical data. Statistical significance was set
as \emph{p} value \textless{} 0.05. OS and AFS for the two groups were
estimated by Kaplan-Meier survival curves with the differences between
the groups analysed by the Breslow-Wilcoxon method.

The study protocol was approved by the Research Ethics Committee at
Galway University Hospital and General Data Protections Regulations were
followed.

\textbf{Results:}

A total of 280 CLI patients were included in the study with 128 (44.6\%)
of patients treated conservatively. The majority of patients were males
(70.7\%), with mean age of 71.6 years. At baseline, the conservative
group were more likely to have Rutherford Class 5 and be diabetic while
they were less likely to be active smokers or have hyperlipidemia (Table
1). There were no significant differences between the conservative and
the revascularization groups in mortality, amputation (major and minor),
overall AFS and one-year AFS rates (Table 2).

Kaplan-Meier cumulative overall survival and AFS over the 3 years
follow-up period of the study demonstrated significant differences
between the conservative and revascularization groups (Log Rank: 0.031
\& 0.045; respectively) (Figure 1 \& 2). This statistical significance
was not detected when one-year AFS was evaluated (Log Rank 0.096)
(Figure 3).

Further evaluation of the clinical outcome of the conservatively treated
group was performed by comparing the baseline characteristics of
patients who recovered to those who had amputation or died during the
follow up period. Recovery was defined as complete resolution of rest
pain for patients with Rutherford class 4 CLI or complete ulcer healing
for Rutherford class 5 patients. In univariate analysis, diabetes and
chronic kidney disease were associated with higher rates of amputation
and/or mortality in CLI patients treated conservatively (Table 3).

\textbf{Discussion:}

Conservative management has been considered a second line management
option for CLI patients after the preferable interventional
revascularization. This was based on the reported high risk of one-year
mortality and amputation associated with untreated CLI {[}8{]}. As both
surgical and endovascular interventions are also associated with high
morbidity and mortality, evidence has emerged recently supporting the
suitability of conservative management as a primary option to achieve
AFS in CLI patients even when revascularization is technically feasible
{[}5{]}.

The current study compared amputation and mortality rates in patients
treated with revascularization and those treated conservatively. The
observed difference in baseline characteristics between the two groups
reflects the current management strategies, where conservative
management is mainly offered to ``no-option'' patients who have more
advanced disease and medical comorbidities.

While resolution of rest pain and ulcer healing are regarded as the
immediate therapeutic targets of CLI management, prevention of
amputation and prolongation of survival are considered the ultimate
desired outcomes {[}3{]}. The results of this study support the argument
that conservative management is comparable to revascularization in terms
of rates of mortality, minor and major amputation, overall AFS and
one-year AFS. Although differences between the two groups were observed
in cumulative OS and AFS, this difference was not observed in the
one-year AFS. Univariate analysis indicates diabetes and chronic kidney
disease as predictors of poor outcome in the conservatively treated
group. These findings support the argument that conservative management
may be an appropriate primary treatment to achieve AFS in selected CLI
patients, as already reported by several other studies {[}5, 6, 9,
10{]}.

The results of the current study are limited by the observational nature
of the study, therefore further studies are required to inform the most
suitable criteria for identifying patients who can be treated
conservatively even when revascularization is technically achievable.

\textbf{Conclusion:}

Conservative management can be a suitable management option to achieve
one-year AFS for some CLI patients. Further studies are needed to
identify robust clinical criteria for identifying patients who will
benefit from conservative management.

\textbf{References:}

1. Norgren, L., et al., \emph{The Next 10 years in the Management of
Peripheral Artery Disease: Perspectives from The `PAD 2009'
Conference.}European Journal of Vascular \& Endovascular Surgery,
2010.\textbf{40} (3): p. 375-380.

2. Norgren, L., et al., \emph{Inter-Society Consensus for the Management
of Peripheral Arterial Disease (TASC II).} Journal of Vascular Surgery,
2007. \textbf{45} (1): p. S5-S67.

3. Varu, V.N., M.E. Hogg, and M.R. Kibbe, \emph{Critical limb
ischemia.}Journal of Vascular Surgery, 2010. \textbf{51} (1): p.
230-241.

4. Bradbury, A.W., et al., \emph{Bypass versus Angioplasty in Severe
Ischaemia of the Leg (BASIL) trial: Analysis of amputation free and
overall survival by treatment received.} Journal of Vascular Surgery,
2010. \textbf{51} (5): p. 18S-31S.

5. Santema, T.B., et al., \emph{Not All Patients with Critical Limb
Ischaemia Require Revascularisation.} European journal of vascular and
endovascular surgery, 2016. \textbf{53} (3): p. 371-379.

6. Benoit, E., et al., \emph{Improved amputation-free survival in
unreconstructable critical limb ischemia and its implications for
clinical trial design and quality measurement.} Journal of Vascular
Surgery, 2012. \textbf{55} (3): p. 781-789.

7. Mohamed, S.A., et al., \emph{Autologous bone marrow mesenchymal
stromal cell therapy for ''no-option'' critical limb ischemia is limited
by karyotype abnormalities.} Cytotherapy, 2020. \textbf{22} (6): p.
313-321.

8. Abu Dabrh, A.M., et al., \emph{The natural history of untreated
severe or critical limb ischemia.} Journal of vascular surgery,
2015.\textbf{62} (6): p. 1642-1651.e3.

9. Steunenberg, S.L., et al., \emph{Quality of Life and Traditional
Outcome Results at 1 Year in Elderly Patients Having Critical Limb
Ischemia and the Role of Conservative Treatment.} Vasc Endovascular
Surg, 2020. \textbf{54} (2): p. 126-134.

10. Thomas, A.R., et al., \emph{Conservative Treatment in Selected
Patients with Severe Critical Limb Ischemia.} World Journal of Surgery,
2015. \textbf{39} (8): p. 2090-2095.

\textbf{Table 1:} \textbf{Demographic data and patient's
characteristics}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Total Group (n = 280)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Conservative (n = 125)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Revascularization (n = 155)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\emph{P}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age (mean \selectlanguage{ngerman}± SD)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
71.6 \selectlanguage{ngerman}± 11.6\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
73 \selectlanguage{ngerman}± 11.9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
70.4 \selectlanguage{ngerman}± 11.3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.062\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Sex (\%) Males Females\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
198 (70.7\%) 82 (29.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
91 (72.8\%) 34 (27.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
107 (69\%) 48 (31\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.512\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Rutherford (\%) 4\\
5\\
6\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
76 (27.1\%) 196 (70\%) 8 (2.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
20 (16\%) 100 (80\%) 5 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
56 (36.1\%) 96 (61.9\%) 3 (2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.0003\textsuperscript{*}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Smoking (\%) Non Past Current\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
125 (44.6\%) 93 (33.3\%) 62 (22.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
71 (56.8\%) 35 (28\%) 19 (15.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
54 (34.9\%) 58 (37.4\%) 43 (27.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.0008\textsuperscript{*}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Diabetes (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
111 (39.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
62 (49.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
49 (31.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0031\textsuperscript{*}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cardiac disease (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
137 (48.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
62 (49.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
75 (48.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.904\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cerebrovascular disease (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
46 (16.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
22 (17.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24 (15.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.746\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hypertension (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
177 (63.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
78 (62.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
99 (63.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.805\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hyperlipidemia (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
107 (38.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
39 (31.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
68 (43.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.036\textsuperscript{*}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
COPD/Asthma (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
48 (17.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19 (15.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (18.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.524\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Chronic kidney disease (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58 (20.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32 (25.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (16.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.077\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2: Clinical Outcomes}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
outcome\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Total Group (n = 280)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Conservative (n = 125)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Revascularization (n = 155)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\emph{p}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mortality\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
45 (16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (20.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19 (12.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0711\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Major Amputation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
44 (15.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20 (16\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24 (15.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textgreater{} 0.9999\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Minor Amputation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67 (23.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (23.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
38 (24.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.8881\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Amputation-free survival\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
193 (68.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
84 (67.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
119 (76.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.0813\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
One-year AFS\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
211 (75.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
89 (71.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
122 (78.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.1642\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3:} Comorbidities of conservatively managed patients\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Recovered (n=27)\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Amputation and/or Death (n= 41)\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\emph{P}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age (mean \selectlanguage{ngerman}± SD)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
71 \selectlanguage{ngerman}± 13.5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
74 \selectlanguage{ngerman}± 11.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.332\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Sex (\%) Males Females\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22 (81.5\%) 5 (18.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
31 (75.6\%) 10 (24.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.766\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Rutherford (\%) 4\\
5\\
6\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 (29.6\%) 19 (70.4\%) 0 (0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (12.2\%) 33 (80.5\%) 3 (7.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.127\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Smoking (\%) Non Past Current\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (40.7\%) 10 (37\%) 6 (22.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
22 (55\%) 8 (20\%) 10 (25\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.306\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diabetes (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (22.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26 (64.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.001\textsuperscript{*}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cardiac disease (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (40.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25 (61\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.138\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cerebrovascular disease\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (14.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (16.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.999\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hypertension (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (59.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23 (56.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.999\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hyperlipidemia (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (29.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (26.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.999\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
COPD/Asthma (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (11\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10 (24.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.129\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Chronic kidney disease (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (11\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (39\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.014\textsuperscript{*}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure 1:} \textbf{Kaplan-Meier cumulative overall survival}

Figure 1: Kaplan-Meier curve of overall survival comparing the two
groups (Log Rank 0.031)

\textbf{Figure 2: Kaplan Meier for amputation-free survival}

Figure 2: Kaplan-Meier curve of amputation-free survival comparing the
two groups (Log Rank 0.045)

\textbf{Figure 3: Kaplan Meier for one-year amputation-free survival}

Figure 3: Kaplan-Meier curve of one-year amputation-free survival
comparing the two groups (Log Rank 0.096)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-2/figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-3/figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

