Inclusion criteria patient.

Patients of 65 years or older with CLTI who are planned for revascularization are eligible to participate in this study. According to the guidelines of the European Society of Vascular Surgery (ESVS) the diagnosis of CLTI is based on the following criteria [8]:

• Anamnestic complaints of ischemic rest pain or night pain (Rutherford stage 4) OR (Minor) tissue loss, non-healing ulceration or gangrene of any part of the foot (Rutherford stage 5), present for at least two weeks [40].

AND

• Impaired perfusion, quantified by:
  • Absolute ankle pressure < 50 mmHg
  • Absolute toe pressure < 30 mmHg
  • Ankle-brachial index (ABI) < 0.4
  • Flat or barely pulsatile ankle or metatarsal pulse volume recording (PVR) waveforms

Exclusion criteria patient.

A potential participant who meets any of the following criteria will be excluded from participation in this study:

• Patients undergoing conservative therapy (including optimal pharmacological treatment of pain, intensive wound care and minor amputations).
• Need for urgent surgery or endovascular therapy within 2 weeks, based on a Wound, Ischemia, foot Infection (WIfI) classification score of either [6]:
  • ‘Wound’ score of W = 3
  • ‘foot Infection’ score of fI = 3
• Patients who are unable to complete questionnaires, due to either lingual or cognitive incompetence.

Inclusion criterium informal caregiver.

Adults serving as the primary IC of an enrolled CLTI-patient will be asked to participate in this study. A primary IC is defined as the individual most involved in caring for the CLTI-patient and supporting at least one instrumental activity of daily living of the patient or the contact assisting in treatment-related decisions.

Exclusion criterium informal caregiver.

Primary ICs who are unable to complete questionnaires, due to either lingual or cognitive incompetence will be excluded from the study.

Primary outcome.

The primary outcome of this study is the length of stay (LOS), defined as the number of days a patient is admitted to the hospital after revascularization. If patients are admitted and discharged on the same day, LOS is counted as one day. LOS will be extracted from the electronic patient dossiers.

Secondary outcomes.

Secondary outcome measures are divided in four categories:

• Clinical and healthcare related outcomes: postoperative complications, hospital readmission rate, 30-day and 6-month mortality, cost-effectiveness (using the iMTA Medical Consumption Questionnaire (iMCQ) [41] and the EQ-5D-5L questionnaire [42])
• Patient and informal caregiver reported outcomes:
  • Quality of life of both patient and their IC (WHOQoL-BREF) [43]
  • Health related quality of life of patients (EQ-5D-5L) [42]
  • Burden on the IC (CSI) [44]
• Shared decision making
  • The level of perceived SDM of the patient and their IC (CollaboRATE) [45]
  • Perceived and preferred roles in decision making (DM) of the patient and their IC (ACPS) [46]
  • Preferred participation in SDM of the patient and their IC (PICS) [47]
• Study specific outcomes in the intervention group: compliance to the prehabilitation program and process evaluation of the prehabilitation program after 6 months, using effect evaluation forms designed by the research group, see ‘S3 File. Process evaluation questionnaires POCI-study’.

Of all secondary outcomes, only minor complications (Clavien Dindo classification I and II), quality of life and health related quality of life are confirmatory outcomes. All other secondary outcomes require bigger sample sizes to detect a difference with reasonable power and are therefore exploratory endpoints (all preliminary calculations were conducted from https://sample-size.net)

Participant screening and recruitment.

In all three participating centers, patients of 65 years or older with suspected CLTI, will be examined on the outpatient clinic by a vascular surgeon. Confirmation of the diagnosis is based on the ESVS guidelines [8]. The severity of CLTI at initial presentation is scored by using the Rutherford and WIfI-classification [6]. Additional imaging is requested by the vascular surgeon and may be performed by duplex, Magnetic Resonance Angiography or Computed Tomography Angiogram. Vascular pathology will be scored using the Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease II (TASC-II) and description of the crural outflow in 1, 2 or 3 arteries [7,9,48]. All patients with newly diagnosed CLTI, who are likely to require surgical or endovascular revascularization and who meet the eligibility criteria, are invited to participate in the study. Patients’ primary IC will also be invited to participate in the study. Patients remain eligible, even if their primary IC declines participation. Primary ICs can only be included in combination with a patient and are automatically assigned to the same study group as the patient. Written and verbal study information is provided by the vascular surgeon, a researcher or a vascular nurse practitioner (VNP). Questions will be answered and potential participants are asked if they are willing to participate in the study. Patients and their IC are offered sufficient time to process the study information and consider participation. If needed, telephone contact is made by the researcher or VNP the day after the outpatient clinic visit.

Informed consent and randomization.

Patients who agree to participate, provide oral informed consent, after which they are immediately randomized to the prehabilitation group or the control group. Enrollment of the patient and their IC occurs on the day of, or the day after, the first outpatient clinic visit. This ensures that prehabilitation starts within a few days, parallel to the treatment planning, without delaying the moment of revascularization. All participants will be scheduled within a few days for an appointment with the VNP or researcher for a general health screening (T0), during which written informed consent will be obtained.

Participants are randomized to either the prehabilitation group or the control group using a variable block randomization (2:4:6) procedure to minimize the risk of unequal group sizes and to reduce predictability of assignments. To further ensure comparability between study arms, randomization is stratified by the participating hospital, to eliminate systematic imbalances between hospitals and enhance internal validity. The randomization procedure will be carried out using the validated electronic data capture system Castor EDC. This study is not subject to blinding due to the extensive and active nature of the intervention.

General health screening (T0).

All included patients undergo a general health screening by a trained VNP or researcher as part of the standard care. The content and details of this assessment are shown in Fig 1. Patients are requested to bring their primary informal caregiver, to optimize the (hetero)anamnesis, to ensure understanding of the provided information, and assess the availability of informal support. At the end of the visit all patients and informal caregivers are asked to complete the baseline questionnaires (Fig 1). After completing the questionnaires, patients in the control group conclude their appointment. Patients randomized to the intervention group proceed with the MMPP.

Study intervention–Multimodal multicomponent prehabilitation program.

The MMPP has a minimum duration of two weeks, considering both the expected time needed to achieve clinically meaningful results and the time in which treatment is planned and must take place [33]. Patients’ IC will be an active participant in the MMPP, as they can supervise physical training at home, help patients with following advices and can participate in decision making. The program consists of six components: a mandatory visit to a physiotherapist, and, if indicated, referral to a dietician, geriatrician or a smoking-cessation coach; ferric carboxymaltose infusion or pre-arranged homecare. In addition, to reduce the burden on patients and their IC, all required appointments are combined into a single morning or afternoon if possible. Specific indications and details of the components of the MMPP are shown in Table 1. At the start of the visit to the MMPP, all patients receive an information brochure of the prehabilitation outpatient clinic, containing general information of the outpatient clinic, the physiotherapy handbook and the dietetics information brochure (see S4. File Information brochure outpatient clinic).

1. I. Physiotherapist

Immediately after the general health screening, patients in the intervention group are screened by a physiotherapist. Patients’ physical state, muscle strength and cardiopulmonary condition are examined by conducting several tests, as described in Table 1. All tests are widely used and chosen taking into account the pain-limited performance capacity of most CLTI-patients. The TUG-test and grip strength are performed in agreement with the geriatricians to give an indication of patients’ level of frailty [49]. Based on the results of the tests, patients are provided with a personalized, home-based training schedule, targeting muscle strength, cardiopulmonary condition and improving patients’ ability to conduct transfers. To ensure uniformity of the provided screening, advices and the amount and intensity of the prescribed exercises in all participating centers, the physiotherapy handbook was designed (S4. File Information brochure outpatient clinic). To increase compliance, patients are provided with a diary to track their daily activities. Their IC is instructed to support completing the exercises and to help keep track of patients’ compliance in their diaries.

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Table 1. Indications and details of the components of the MMPP.

https://doi.org/10.1371/journal.pone.0354344.t001

1. II. Geriatrician

If indicated (see Table 1) patients are referred to a geriatrician. Patients undergo a comprehensive geriatric assessment (CGA) to assess frailty and the risk of developing a delirium. Previous studies showed that performing a preoperative CGA in older vascular surgery patients is associated with shorter LOS and lower complication rates [50,51]. Based on CGA findings, the geriatrician provides tailored information to patients and their IC, including preventive measures for functional decline and delirium after revascularization. Furthermore, if indicated based on the results of the biochemistry tests, patients are prescribed supplementary vitamins.

1. III. Dietician

If indicated (see Table 1), the dietician assesses patients’ nutritional status. All patients are provided with oral and written information on preoperative optimization of their diet, mainly focused on a sufficient protein intake (see S4 File Information brochure outpatient clinic). Protein targets are calculated as 1,2g/kg body weight, taking into account patients’ BMI and renal function and adjusted accordingly if necessary. If patients reach only 50–75% of their protein target, they initially obtain recommendations on a high protein diet. In case those recommendations are insufficient, oral nutritional supplements are prescribed and patients receive a control appointment with the dietician.

1. IV. Smoking-cessation coach

Active smokers are offered a referral to a smoking-cessation coach to receive guidance in reducing nicotine abuse. The coach intends to see patients within three days after referral and provides individualized or group-based guidance, depending on patients’ preferences.

1. V. Ferric carboxymaltose infusion

In the presence of anemia, patients receive a dose of 1000 mg intravenous ferric carboxymaltose in 15 minutes, administered during a day-care admission. If hemoglobin concentration is below 6.2, patients are referred to internal medicine for further evaluation of possible underlying diseases. A previous study evaluating the effect of ferric carboxymaltose infusion as part of a prehabilitation program for older surgical patients, demonstrated the administration is safe and eliminates differences in hemoglobin concentration at discharge between patients who initially presented with anemia and those without anemia, regardless of iron concentration at initial presentation [52].

1. VI. Pre-arranged homecare

If problems are expected in patients’ home situation after discharge from the hospital, for example due to functional decline after revascularization or an overburdened IC, pre-arranged homecare is initiated by the VNP or researcher.

Multidisciplinary meeting.

All patients are discussed in a weekly, multidisciplinary meeting with vascular surgeons and interventional radiologists. This session results in a treatment advice for either surgical or endovascular revascularization, based on the type of pathology, the imaging findings and the results of the general health screening. If conservative treatment is proposed, or patients require primary major amputation, they are excluded from this study.

Second visit to the vascular surgeon (TSDM0).

The vascular surgeon will discuss the proposed treatment plan with the patient and their IC in a second outpatient clinic visit. At the end of the visit, both patient and their IC are asked to complete the questionnaires regarding the SDM process (Fig 1). Together with the questionnaires, explicit instructions are provided to complete the questions solely based on their experiences with the visit to the vascular surgeon.

Hospital admission (T1).

At hospital admission, approximately two weeks after inclusion, patients in the intervention group complete a process evaluation form to assess adherence and experiences with the prehabilitation program (S3 File. Process evaluation questionnaires POCI-study). Patients’ diaries serve as a reference throughout this evaluation.

Follow up 6 months (T2).

All patients receive postoperative follow-up, according to the local hospital guidelines. At six months after revascularization, patients and ICs are invited by post to complete the same questionnaires they completed during the general health screening. In addition, participants in the intervention group are asked to complete another process evaluation form, evaluating their experiences and preferences with the MMPP on the long-term (S3 File. Process evaluation questionnaires POCI-study).

Sample size.

Sample size was calculated for the primary outcome LOS. Previous observational data showed that prehabilitation was associated with a difference of 2 versus over 4 days of hospital stay in the prehabilitation group compared to the control group [33]. A halving in length of stay requires 54 patients in total (27 per group, assuming a SD of log (LOS) of 0.9, as in the previous study). With a total of 300 patients, 100 from each participating center, the study has 80% statistical power with 2-sided alpha set at 5% to detect a 25% reduction (factor 0.75) in LOS. Sample size calculation was done using the online sample size calculators at https://sample-size.net/.

Statistical analyses.

Statistical analyses will be performed using IBM SPSS statistical software (SPSS Inc., Chicago, Illinois, USA). Results of categorical data variables are described in frequencies with percentages and differences will be tested using the Chi-square test. Ordinal variables will be tested using the Mann-Whitney U-test. Adjusted analysis will be performed using regression analysis with prognostic baseline characteristics (e.g., gender, age). Continuous data are described as median (interquartile range) and Mann-Whitney U-tests will be performed to test for group differences. Continuous outcomes are analyzed using a linear regression model, whereas binary outcomes are analyzed by using a logistic regression model. To assess the primary study parameter LOS, a linear regression model including important covariates (such as age, gender, surgical history, comorbidities, use of medication, smoking status, use of alcohol, home situation) that may contribute to the outcome of LOS will be used. LOS is expected to be skewed; therefore, a log-transformation will be performed. Hospital site will be a stratification factor in the regression analysis. Repeated measures will be analyzed with mixed effect models with random effects per patient to address patient clustering. Missing data will be studied for specific patterns of occurrence, and multiply imputed. The primary data analysis will be done according to the intention-to-treat concept. Secondary, a per protocol analysis will be performed.

We conducted power calculations for the secondary outcome’s minor complications, quality of life and health related quality of life at https://sample-size.net. In the previous study by Meulenbroek et al. [33] prehabilitation was associated with a difference in minor complications of 12% (26% vs 14%). This difference would require a sample size of 346. With 300 patients we will have reasonable power (69%) for detecting a difference in minor complications.

Quality of life (WHOQOL-BREF) and health related quality of life (EQ-5D-5L) will be evaluated at baseline (pre-intervention) and at 6 months post-operatively. With a total sample size of 300, this study has a statistical power of 80% (two-sided, α = 0.05) to detect a standardized Effect Size (Cohen’s d) of 0.36 or larger on the domains of the WHOQOL-BREF, the EQ-5D index score and the EQ-VAS. Therefore, the sample size is considered adequate to detect small-to-medium clinical effects. Interpretation of the results will focus on the Minimal Clinically Important Difference (MCID). The exact MCID for both the WHOQOL-BREF and the EQ-5D-5L scores in CLTI patients has not been decided yet. Therefore, based on an earlier systematic review by Norman et al. [9] we will consider an effect size of 0.5 SD as clinically relevant.

For the outcomes with limited power for comparative analyses, we will provide point estimates with 95% confidence intervals to caution against overinterpretation of negative findings as proof of equivalence.

Interim analysis.

Interim analysis shall be conducted for the meetings of the data safety monitoring board (DSMB) and will focus on monitoring complication rates. Data will be presented descriptively as percentages for each group.

Cost-effectiveness analyses.

A comprehensive economic evaluation will be performed, including a cost analysis from hospital perspective, a cost-utility analysis from societal perspective (CUA, i.e., costs per QALY), and a budget impact analysis (BIA). In all three analyses, care with and without prehabilitation will be compared according to intention to treat.

• For the hospital cost analysis, six-month hospital costs, including interventions and stay, will be assessed from the financial records of all three participating centers.
• For the CUA, costs from a societal perspective will be compared. Costs outside the hospital such as wound care, physiotherapy, home care and informal care will be assessed using a shortened version of the iMCQ questionnaire at six months [41]. Care will be valued according to Dutch reference prices, including travel costs. Productivity costs are excluded, because of the low labor participation in this 65 + study population. QALYs will be calculated using the Dutch tariff for the five-level EuroQoL EQ-5D (assessed at 0, and 6 months), with a sensitivity analysis using the EuroQol visual analogue scale [42]. Incremental average six months costs and QALYs will be compared using net-benefit analysis with multiple imputation to account for missing data.
• The BIA will estimate the financial impact of different implementation scenarios at the national level. The analysis will be conducted from the perspectives of society, hospital and insurers, using the ZonMw BIA guideline and tool [53]. The BIA will be based on the costs as estimated during the study, and the expected numbers of patients in the Netherlands. Healthcare will be valued according to cost prices (for the societal perspective) or NZa prices (for the hospital and insurer perspectives). Costs will be estimated per 1-year budget period for a time horizon of five years, assuming 50% to 100% implementation after four years.

Data safety monitoring board (DSMB).

An independent DSMB will be established for this trial. None of the DSMB members are involved in the study in any other capacity.. The DSMB will monitor participant safety throughout the trial, primarily based on the results of the interim-analyses. The DSMB is responsible for assessing whether the MMPP continues to meet safety standards and for issuing recommendations regarding continuation, modification or early termination of the study. Alle recommendations by the DSMB will be communicated to the study sponsor and the principal investigators of all participating centers. The DSMB may recommend premature termination of the study if any notable negative effects emerge in the intervention group, compared to the control group.

Data handling and storage.

Data will be handled confidentially. Clinical data will be collected from the electronic medical records and questionnaires by the PhD student or researchers. Completed questionnaires and informed consent forms will be securely stored in locked cabinets at each participating site, accessible only by authorized personnel. A dedicated digital study folder will be created in each participating hospital in which the digital data is saved. Organization and storage of de-identified data and questionnaires will be managed using Castor SMS and Castor EDC, a clinical data management platform. Data handling procedures adhere to the Dutch “Uivoeringswet AVG, UAVG” (Act on Implementation of the General Data Protection Regulation).

Participants may withdraw from the study at any time after providing consent. Withdrawn subjects will not be replaced and data collected prior to withdrawal will remain part of the study dataset. Routinely collected data regarding LOS, mortality, hospital readmission rate and complications, will continue to be extracted from patients’ electronic medical records.

Data monitoring.

Monitoring of informed consent and study data will be performed by the project leader, principal investigators and designated researchers at the participating centers. An independent data monitor will conduct annual site visits to ensure data quality, accuracy and protocol adherence. During these visits information will be reviewed regarding the date of inclusion of the first participant, number of participants included and number of participants that have completed the trial, serious adverse events, other relevant issues or deviations, and protocol modifications.