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Vessel Plus 2022;6:9. 10.20517/2574-1209.2021.79 © The Author(s) 2022.
Open Access Original Article

Survival and clinical outcomes of diabetic peripheral artery disease patients following a pain-free home-based walking program

1Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara 44121, Italy.

2Unit of Vascular and Endovascular Surgery, University Hospital of Ferrara, Ferrara 44124, Italy.

3Department of Medical Statistics, University Hospital of Ferrara, Ferrara 44124, Italy.

4PhD program in Sustainability Environmental and Wellbeing, University of Ferrara, Ferrara 44121, Italy.

5Vascular Diseases Center, University of Ferrara, Ferrara 44124, Italy.

6Unit of Physical and Rehabilitation Medicine, University Hospital of Ferrara, Ferrara 44124, Italy.

7Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.

Correspondence to: Dr. Nicola Lamberti, Department of Neuroscience and Rehabilitation, University of Ferrara, Via Luigi Borsari 46, Ferrara 44121, Italy. E-mail:lmbncl@unife.it

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    Academic Editors: Giuseppe Biondi-Zoccai, Elena Cavarretta, Alexander D. Verin | Copy Editor: Yue-Yue Zhang | Production Editor: Yue-Yue Zhang

    © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


    Aim: We retrospectively examined the impact on the rate of survival of pain-free home-based exercise in diabetic peripheral artery disease patients compared to patients receiving usual care.

    Methods: In total, 202 patients at Fontaine’s Stage II with diabetes were studied. Half were enrolled in a structured home-based exercise program (E), whereas the other half received walking advice as the active control group (C). Long-term clinical outcomes at five years were gathered from the Emilia-Romagna Health Service Registry, with survival probability selected as the primary outcome.

    Results: At baseline, the two groups did not differ for any demographic or clinical characteristics. High adherence to the program was recorded in Group E (88% of home-walking sessions executed, with an average distance walked during the program of 174 km). After five years, a survival rate of 90% for Group E and 60% for Group C was observed, with a significantly (P < 0.001) higher mortality risk for Group C [Hazard ratio (HR) = 3.92]. Additionally, among secondary outcomes, Group E showed a significantly (P = 0.048) lower rate of peripheral revascularizations than Group C (15% vs. 24%, respectively; HR = 1.91), all-cause hospitalizations (P = 0.007; 61% vs. 80%, HR = 1.58), and amputations (P = 0.049; 6% vs. 13%, HR = 2.47). In a Cox multivariate-proportional regression model of the entire population, the predictors of survival probability were age (HR = 1.05), Charlson index (HR = 1.24), lower ankle-brachial index (HR = 6.66), and control group (HR = 4.99).

    Conclusion: A simple sustainable program aimed at improving mobility of diabetic patients with claudication at high cardiovascular risk was associated with better survival and long-term clinical outcomes.


    Atherosclerotic peripheral artery disease (PAD) is a highly prevalent and undertreated global disease, with a negative association with premature cardiovascular events and death[1]. Atherosclerotic lesions in the arteries of the lower limbs result in impaired blood flow to the legs of patients who experience cramping pain during walking and a limitation of their daily activities[2-3].

    In patients with diabetes, PAD is highly prevalent[4], and it represents the most common manifestation of cardiovascular diseases. Indeed, PAD in diabetic subjects reflects a systemic atherosclerotic disease with peculiar characteristics, such as a high incidence of vascular calcifications[5], rapid progression toward more severe PAD stages, and prevalent involvement of distal and bilateral arteries[5]. All these factors are ultimately associated with worst long-term clinical outcomes[4,6-7] including a high risk of amputations[8], unfavorable cardiovascular outcomes, and higher mortality in diabetic PAD patients as compared to those in non-diabetic PAD patients[9-10].

    The first line of treatment in these individuals is lifestyle modification and exercise therapy[11], with supervised treadmill exercise performed at an intensity such as to evoke moderate to severe pain as a first-line recommendation for patients with PAD and intermittent claudication[12].

    However, the presence of pain during walking might reduce adherence to programs[12], as do other barriers such as costs, travel, and access. The presence of diabetes may also attenuate improvements in walking performance in patients with PAD following exercise[11]. Moreover, repeated cycles of exercise-induced ischemia followed by reperfusion may be associated with signs of muscular damage, an increase in inflammatory markers and reactive oxygen species production, and structural and metabolic changes in the muscle with reduced strength and function[13-16].

    In addition, patients with type 2 diabetes need to be carefully checked and monitored before engaging in an exercise program[7]. In particular, patients severely detrained should start exercise at low intensity with close supervision by healthcare professional, aiming at integration of regular physical activity into daily routine[7]. However, regardless of exercise length and modality, regular intensive walking exercise in more effective than usual care[17].

    More than a decade ago, a structured low-intensity, pain-free program prescribed at hospital and executed at home was developed and introduced into clinical practice for patients with PAD[18-20]. The Test in-Train out program (TiTo) proved itself to be effective on functional capacity and quality of life in patients with claudication, even in the presence of comorbidities[21,22], when compared to surgical revascularization[23], with favorable long-term clinical outcomes[24-25]. The program was also successfully translated to stroke survivors, patients with end-stage kidney disease, and people with multiple sclerosis[26-30].

    Therefore, given the high risk of mortality reported in diabetic PAD patients and the protective effect of exercise programs, we hypothesize that a different risk of mortality rates at five years would be observable in diabetic PAD patients enrolled or not into an exercise program.

    The aim of this retrospective study was to examine the rate of survival, hospitalizations, and lower extremity amputations in a cohort of diabetic PAD patients enrolled in the TiTo home-based exercise program compared to another matched cohort of diabetic PAD patients acting as a control group.


    Study design and setting

    This single-center cohort study was conducted at University Hospital of Ferrara, Italy, between 2013 and 2014. The study was approved by The Local Ethics Committee (CE-AVEC) (approval number 277/2019), but written informed consent was not attainable from all participants.

    This study retrospectively analyzed a prospectively collected database of patients with PAD who were recruited at Unit of Vascular Surgery and referred for the training program at the Unit of Rehabilitation Medicine. A follow-up period of five years was considered. Long-term outcomes were gathered from the Emilia-Romagna Regional Health Service Registry.


    A cohort of diabetic PAD patients were enrolled in the rehabilitation program. The included patients presented with PAD at Leriche-Fontaine Stage II; diagnosis of type 2 diabetes with habitual use of oral hypoglycemic agents, insulin, or both; and no contraindications to low-intensity exercise training (heart failure, amputations, severe cognitive impairments, etc.).

    During the same temporal frame, a parallel control group of patients with PAD with the same inclusion criteria were also studied from those screened at the outpatients’ clinics of the Department of Vascular Surgery.

    Patients were then classified into two groups according to the study objectives: exercise (E) and control (C).

    Data regarding clinical status (including medication, risk factors, and comorbidities), PAD severity (including type of lesions), and ankle-brachial index were collected from the medical records of each patient. An independent researcher blinded to the group allocations of the patients created the dataset with the clinical information.

    Exercise group: training program

    All patients received the “Test in-Train out” home-based pain-free exercise program[19,20].

    This low-intensity structured exercise program was prescribed during approximately monthly visits at the hospital, and it was executed at home. The program is scheduled with two daily 10 min sessions of intermittent walking (with a 1:1 walk: rest ratio) at a prescribed speed. This training speed, which is converted into a walking cadence (steps/min) and maintained at home by the use of a metronome, was slower than the individual’s walking speed at the beginning and progressively increased weekly. A daily log to monitor the program execution was provided to the patients, and feedback was requested at each hospital visit. The program lasted 6-12 months. Patients were discharged when they perceived a satisfactory upgrade of mobility, and a stable improvement in the pain-free walking distance was attained (e.g., when they reached a measured symptom-free walking speed of normal for sex and age, which was confirmed in two subsequent tests). Discharge was also possible when no changes in walking ability were observed after repeated measurements (e.g., for intercurrent osteoarticular pathologies) or for the impossibility or willingness to exercise or to complete the program. More details on the exercise program are reported elsewhere[19,20].

    Control group

    Patients in the control group who underwent duplex examination without functional assessment were instructed to maintain a healthy and active lifestyle, according to the TASC II guidelines[31]. In detail, patients were advised to perform track walking of sufficient intensity to bring on claudication, followed by rest, over the course of a 30-60 min session, three times per week[31]. A 12-month follow up visit was also scheduled with instrumental and clinical examinations, without intermediate visits.

    After discharge, patients of both groups received recommendations to perform physical activity and to maintain an active and healthy lifestyle, according to the guidelines[31].

    Study outcomes

    Five-year survival probability was the primary outcome. Secondary outcomes included PAD-related lower limb revascularization (including both endovascular and surgical procedures), all-cause hospitalizations, and lower limb amputations (minor or major). Outcomes were considered after the date of the entrance of participants into the program for Group E and after the vascular surgeon’s visit for Group C. A five-year follow up period was obtained for all participants; in the case of death in absence of a precise outcome (e.g., amputation), data were censored at the date of death.

    Statistical analysis

    Data distribution was verified with a Kolmogorov-Smirnov test. Differences in baseline characteristics for the two groups were evaluated with Chi-squared tests, Student’s t-tests, or Mann-Whitney tests, as appropriate.

    Kaplan-Meier estimates of the distribution of time from enrollment to date of death and a log-rank test for trend were used to compare the curves of the patient group.

    Multivariate Cox proportional hazards regression analyses were employed to analyze the effect of several predictor variables on the primary outcome for each group. Because of the limited number of events, multivariate HRs were calculated using a forward approach, with an entry limit of P < 0.05. A P value < 0.05 was considered statistically significant.

    All statistical analyses were performed using MedCalc Statistical Software version 19.8 (MedCalc Software bvba, Ostend, Belgium).


    The clinical records of 416 claudication patients who visited the Department of Vascular Surgery between 2013 and 2014 were analyzed. In total, 196 patients underwent the rehabilitation program, and the remaining patients underwent vascular screening. In total, 214 patients were excluded because they were not diagnosed with diabetes (n = 187) or did not comply with the other inclusion criteria (n = 27). The final sample included 202 diabetic patients with claudication, 101 belonging to Group E and 101 to Group C [Figure 1].

    Figure 1. Flow diagram of the participants.

    At baseline, the two groups did not differ for any demographic or clinical characteristics or in PAD severity [Table 1].

    Table 1

    Baseline comparison of the two study groups

    Exercise (n = 101)Control (n = 101)P
    Age, years69 ± 1069 ± 11n.s.
    Males, n(%)65 (66)70 (71)n.s.
    Risk factors; n (%)
    Smoking86 (85)86 (85)n.s.
    Hypertension80 (79)78 (77)n.s.
    Hyperlipidemia71 (70)63 (62)n.s.
    Diabetes mellitus101 (100)101 (100)n.s.
    Chronic kidney disease34 (34)33 (33)n.s.
    Comorbidities; n (%)
    Ischemic heart disease30 (30)26 (26)n.s.
    Stroke10 (10)15 (15)n.s.
    Pulmonary disease11 (11)18 (18)n.s.
    Neoplastic disease10 (10)18 (18)n.s.
    Age-adjusted charlson index7 ± 28 ± 2n.s.
    Laboratory values
    Hemoglobin, g/dL13.5 ± 1.412.6 ± 1.8n.s.
    Total cholesterol, mg/dL202 ± 69174 ± 50n.s.
    Triglycerides, mg/dL178 ± 98152 ± 81n.s.
    Serum creatinine, mg/dL1.45 ± 0.891.54 ± 1.07n.s.
    Peripheral artery disease
    Lower limbs revascularization15 (10)19 (19)n.s.
    Bilateral disease82 (81)79 (78)n.s.
    ABI more impaired limb0.63 ± 0.160.61 ± 0.19n.s.
    ABI less impaired limb0.85 ± 0.200.78 ± 0.19n.s.

    In addition, the two groups were also balanced for duration of diabetes (E, 5 ± 4 years vs. C, 5 ± 5 years; P = 0.79) and for the proportion of patients with insulin-dependent diabetes (E, 39% vs. C, 41%; P = 0.58).

    Exercise group

    In total, 98 patients in Group E safely completed the training program without any adverse events related to the training; the remaining three patients dropped out for health reasons. The program lasted for a mean of 9 ± 1 months, with a high adherence (mean value of 88% of home-walking sessions executed with respect to the prescribed sessions) and a mean distance walked at home of 174 ± 29 km. Seventy-five patients completed 100% of the training sessions prescribed, while the remaining twenty-three patients performed at least 60% of the program.

    Primary outcome: survival probability

    In the following five years after the baseline data collection, 49 (24%) deaths occurred, 9 in Group E and 40 in Group C, corresponding to a survival rate of 90% for Group E and 60% for Group C.

    Kaplan-Meier analysis [Figure 2] confirmed a significantly (P < 0.001) higher mortality risk for Group C as compared to that for Group E, with an HR of 3.92 [95% confidence interval (CI) 2.24-6.87].

    Figure 2. Kaplan-Meier survival curves in the two groups: exercise (blue) and control (red).

    Secondary outcomes

    A between-group significant difference (log-rank P = 0.048) was also observed for PAD-related revascularizations, with 15 positive cases in Group E and 24 positive cases in Group C, with a HR of 1.91 (95%CI: 1.01-3.62) [Figure 3A].

    Figure 3. Kaplan-Meier curves of the two groups for: revascularization (A); all-cause hospitalizations (B); and amputation (C). The blue lines indicate exercise, while red ones indicate control.

    Additionally, for all-cause hospitalizations, a significant difference was found (log-rank P = 0.007), with 61 hospitalizations in Group E vs. 79 in Group C and an HR of 1.58 (95%CI: 1.13-2.21) [Figure 3B].

    Finally, amputations showed a significant difference (log-rank P = 0.049), despite the few positive cases (6 in Group E and 13 in Group C), with a corresponding HR of 2.47 (95%CI: 1.00-6.10) [Figure 3C].

    A sub-analysis focusing on only hospitalizations for cardiovascular diseases confirmed the previously observed difference for all-cause hospitalizations; in particular, 43 events were found in Group E compared to 64 events in Group C [log-rank P = 0.031; HR = 1.47 (95%CI: 1.07-2.12)].

    Predictors of survival probability

    Multivariate Cox proportional hazard regression models highlighted that age [HR = 1.05 (95%CI: 1.01-1.09)], Charlson index [HR = 1.24 (95%CI: 1.02-1.50)] indicating the presence of comorbidities, ABI of the more impaired limb representing PAD severity [HR = 6.66 (95%CI: 1.37-32.05)], and control group [HR = 4.99 (95%CI: 2.40-10.40)] were the only predictors of mortality in the entire population.

    The multivariate analyses conducted in the two groups confirmed the results observed in the whole population, with age and comorbidities (chronic kidney disease and lung disease) as the more important risk factors for the two groups [Table 2].

    Table 2

    Multivariate hazard ratios (95% confidence interval) of the study variables for the prediction of five-year survival probability in the four patient subgroups

    Exercise (n = 101)Control (n = 101)
    Age1.06 (1.03-1.10)
    Male sex
    Insulin-dependent diabetes
    Chronic kidney disease7.69 (1.58-37.35)
    Ischemic heart disease
    Pulmonary disease6.00 (1.49-24.21)
    Neoplastic disease
    Age-adjusted charlson index
    Lower limbs revascularization
    Bilateral disease
    ABI more impaired limb
    ABI less impaired limb


    The study has shown a reduction in the risk of long-term mortality and adverse vascular outcomes at five years in diabetic PAD patients who were included in the TiTo home exercise program compared to diabetic PAD patients who were simply advised to perform physical activity.

    Patients with symptomatic PAD are exposed to a higher risk of the worst clinical outcomes, including major cardiovascular events and amputations, with five-year cumulative incidences of 63% and 27%, respectively[1]. In the presence of diabetes, the relative risk for mortality has been found to be two- to four-fold greater than that in patients with PAD only[10]. This topic is of importance since the impact on long-term outcomes of the different treatments, including participation in exercise programs, is considered a scientific priority[12]. Peripheral revascularizations have been found to be effective in reducing those relative risks by improving walking ability[6] alone or in combination with exercise programs, which need to be pursued to improve functional capacity, clinical outcomes, and quality of life[5,7]. While several high-intensity programs have been found to be effective[7], based not only on walking but also on cycling or arm-cranking[2], comorbidities such as musculoskeletal complaints, hypertension, peripheral neuropathy, and especially PAD may reduce the response and adherence to exercise training[7]. In addition, program availability, costs, travel, and access to supervised exercise programs are barriers that need to be considered. In the presence of these factors and considering the reduced pain perception of diabetic PAD patients who report claudication at a three-fold higher degree of muscle deoxygenation[32], low-intensity pain-free walking, such as the TiTo program[19-20], should be encompassed to optimize adherence and reduce the possible adverse reactions to training described previously[7].

    The TiTo-structured home-based program has already proved its effectiveness in large populations of patients with PAD[19,20], with a lower relative risk for mortality, revascularizations, and all-cause hospitalizations when both considering those patients who recorded a favorable outcome after the training program[24] and comparing participants to non-participants of the program[25].

    This study confirmed the previous findings in a sample of the population with PAD, including only patients with diabetes. After five years, the mortality rate in the control group was 40%, which is very similar to the percentage recently described[10], but this value dropped to 10% when patients were engaged in the TiTo program, leading to an almost four-fold lower risk. Favorable data were also observed for the secondary outcomes, including PAD-related revascularizations, all-cause hospitalizations, and amputations, with hazard ratios varying from 1.5 to 2 times higher for the control group.

    In a nationwide retrospective analysis after SET programs[33], the five-year freedom from revascularizations was 83%, which is similar to our study (85%) but including a population of claudication patients with and without diabetes. Another study reported similar values (a survival rate of 81% in the SET group) but included only 25% diabetic patients[34]. It is interesting to observe that short bouts of in-home slow interval walking may have an impact on long-term clinical outcomes. However, the increased mobility observed in a poorly active population may represent the explanation. At the end of each week, each patient performed a total of 140 min of walking, corresponding to the amount of physical activity recommended by the guidelines[2,7]. Several factors might also be considered. Low-moderate intensity exercise might improve nitric oxide bioavailability, decrease systemic and local oxidative stress and inflammation[15], and induce vascular adaptations (including angiogenetic factors and lower sympathetic activation of the arteriolar tone) that are not observable following intense exercise[14-15].

    A crucial key factor in making such changes is the high adherence reported, which was favored by the characteristic of the TiTo program, such as its indoor execution (facilitating safety and avoiding any weather interference). In addition, the low intensity of exercise, which does not evoke claudication symptoms, may be another factor favoring adherence, particularly in women[22,35]. Other pain-free protocols have been proposed and found to be effective when performed on a treadmill or using alternative forms of exercise training, such as arm-cranking or leg-cycling ergometers[15,36]. However, these protocols were supervised, with related barriers and limitations in terms of organizational issues (necessity of equipment, presence of a team at the hospital, and patients’ transportation) and patient enrollment (requested ability to walk on a treadmill for least 2 min at 3.2 km/h). Moreover, these programs, unlike TiTo, may not be able to accustom the patient to ground walking and favor long-term autonomous adherence to exercise.

    Several limitations affected the study, including the sample size being limited and the lack of accurate clinical data typical of a retrospective study (e.g., data on glycemic control in the observed period are missing). In addition, the amount of maintenance training suggested to patients at discharge from the exercise program was not collected. To this end, the study reflects a real-world condition (as most of this kind of studies), therefore changes in habits may have occurred randomly in both groups, since some Group E patients may have continued exercising, whereas some of the patients of Group C may have started a rehabilitation program. This fact reduces the potential implication in the results.

    In conclusion, a low-intensity, structured, and home-based program was associated with a lower long-term risk of mortality, invasive vascular treatments, or amputations in patients with PAD and diabetes, even if a direct association could not be claimed. However, mobility recovery, daily exercise appointments, and pain-free maintenance programs may represent favorable factors.

    Properly designed exercise programs in patients affected by PAD and diabetes, as in the study presented, may have a clinical impact; however, their effectiveness needs to be confirmed in randomized trials[37].



    We thank Dr. Corrado Francesco Professione for his contribution to data collection.

    Authors’ contributions

    Conceived and planned the experiments: Lamberti N, Tsolaki E, Gasbarro V, Zamboni P, Straudi S, Manfredini R, Manfredini F

    Carried out the experiments: Lamberti N, Straudi S, Piva G, Manfredini F

    Planned and carried out the long-term data: Tsolaki E, Guerzoni F, Napoli N

    Contributed to the interpretation of the results: Lamberti N, Tsolaki E, Traina L, Gasbarro V, Zamboni P, Manfredini R, Manfredini F

    Took the lead in writing the manuscript: Lamberti N, Manfredini F

    All authors provided critical feedback and helped shape the research, analysis and manuscript.

    Availability of data and materials

    The dataset of the study is available upon request to the corresponding author.

    Financial support and sponsorship


    Conflicts of interest

    All authors declared that there are no conflicts of interest.

    Ethical approval and consent to participate

    The study was performed in accordance with the Declaration of Helsinki and approved by the CE-AVEC Ethics Committee (number 277/2019).

    Consent for publication

    Not applicable.


    © The Author(s) 2022.


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    Cite This Article

    OAE Style

    Lamberti N, Tsolaki E, Guerzoni F, Napoli N, Traina L, Piva G, Gasbarro V, Zamboni P, Straudi S, Manfredini R, Manfredini F. Survival and clinical outcomes of diabetic peripheral artery disease patients following a pain-free home-based walking program. Vessel Plus 2022;6:9. http://dx.doi.org/10.20517/2574-1209.2021.79

    AMA Style

    Lamberti N, Tsolaki E, Guerzoni F, Napoli N, Traina L, Piva G, Gasbarro V, Zamboni P, Straudi S, Manfredini R, Manfredini F. Survival and clinical outcomes of diabetic peripheral artery disease patients following a pain-free home-based walking program. Vessel Plus. 2022; 6:9. http://dx.doi.org/10.20517/2574-1209.2021.79

    Chicago/Turabian Style

    Lamberti, Nicola, Elpiniki Tsolaki, Franco Guerzoni, Nicola Napoli, Luca Traina, Giovanni Piva, Vincenzo Gasbarro, Paolo Zamboni, Sofia Straudi, Roberto Manfredini, Fabio Manfredini. 2022. "Survival and clinical outcomes of diabetic peripheral artery disease patients following a pain-free home-based walking program" Vessel Plus. 6: 9. http://dx.doi.org/10.20517/2574-1209.2021.79

    ACS Style

    Lamberti, N.; Tsolaki E.; Guerzoni F.; Napoli N.; Traina L.; Piva G.; Gasbarro V.; Zamboni P.; Straudi S.; Manfredini R.; Manfredini F. Survival and clinical outcomes of diabetic peripheral artery disease patients following a pain-free home-based walking program. Vessel Plus. 20226, 9. http://dx.doi.org/10.20517/2574-1209.2021.79




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