|Year : 2019 | Volume
| Issue : 2 | Page : 46-53
Multidisciplinary therapeutic and active follow-up protocols to reduce the rate of amputations and cardiovascular morbidities in patients with critical limb ischemia: IRANCLI study design and rationale – A prospective single-center registry in Iran
Omid Shafe1, Jamal Moosavi1, Seifollah Abdi1, Hosein Ali Basiri1, Hamidreza Pouraliakbar2, Ali Setayesh2, Sara Yasini Ardakani2, Saman Alilou3, Shirin Rafatnia3, Hooman Bakhshandeh2, Farhad Jalili2, Parham Sadeghipour1
1 Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
3 Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
|Date of Submission||26-Aug-2019|
|Date of Decision||26-Aug-2019|
|Date of Acceptance||03-Sep-2019|
|Date of Web Publication||03-Oct-2019|
Dr. Parham Sadeghipour
Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran
Source of Support: None, Conflict of Interest: None
Objectives: The endovascular treatment (EVT) of patients with critical limb ischemia (CLI) has received considerable interest in recent years and has significantly affected the associated amputation and survival rates. Nonetheless, that this management modality may be influenced by various logistical and regional situations prompted us to design a local registry to evaluate its applicability and efficacy in our community.Methods: The IRANCLI study is a prospective, observational study that has been established as a registry. The therapeutic and follow-up protocols of this study have been approved by a multidisciplinary team. Recruited patients with CLI are followed up after in-hospital therapeutic management, endovascular revascularization, or minor amputations or debridement in cases with ulcers. The follow-up consists of active monitoring to spot patients with a recurrence of CLI signs and symptoms at early stages. Within 3 years, eligible patients are recruited to the study and are followed up for 3 years. Analyses are carried out to evaluate outcomes – comprising major adverse limb events (the primary outcome), amputation-free survival, limb salvage, event-free survival, major adverse cardiovascular and cerebrovascular events, 30 days' postprocedural adverse events, and procedural success. The predictors of procedural failure and long-term follow-up adverse events are assessed. Result and Conclusion: The IRANCLI study evaluates postendovascular revascularization outcomes and the long-term follow-up of patients with CLI. Uncovering the predictors of EVT failure and adverse events during the follow-up may improve the prospect of cases with CLI by streamlining the determination of both the patients who would benefit the most from EVT and those who would need a closer active follow-up.
Keywords: Amputation, critical limb ischemia, peripheral artery disease, revascularization, toe-brachial index
|How to cite this article:|
Shafe O, Moosavi J, Abdi S, Basiri HA, Pouraliakbar H, Setayesh A, Ardakani SY, Alilou S, Rafatnia S, Bakhshandeh H, Jalili F, Sadeghipour P. Multidisciplinary therapeutic and active follow-up protocols to reduce the rate of amputations and cardiovascular morbidities in patients with critical limb ischemia: IRANCLI study design and rationale – A prospective single-center registry in Iran. Res Cardiovasc Med 2019;8:46-53
|How to cite this URL:|
Shafe O, Moosavi J, Abdi S, Basiri HA, Pouraliakbar H, Setayesh A, Ardakani SY, Alilou S, Rafatnia S, Bakhshandeh H, Jalili F, Sadeghipour P. Multidisciplinary therapeutic and active follow-up protocols to reduce the rate of amputations and cardiovascular morbidities in patients with critical limb ischemia: IRANCLI study design and rationale – A prospective single-center registry in Iran. Res Cardiovasc Med [serial online] 2019 [cited 2020 Feb 26];8:46-53. Available from: http://www.rcvmonline.com/text.asp?2019/8/2/46/268476
| Introduction|| |
Critical limb ischemia (CLI) is the most advanced form of peripheral artery disease and is classified as asymptomatic, severe claudication and rest pain, and tissue loss., The prevalence of peripheral artery disease is between 3% and 10% in the general population and up to 20% in individuals older than 70 years. Almost 1%–3% of patients with peripheral artery disease may present with CLI. The predisposing factors of CLI are advanced age, obesity, sedentary lifestyle, diabetes mellitus, and chronic kidney disease. The increase in the prevalence of these conditions in recent years has inevitably brought about a rise in the prevalence of CLI.,
CLI is associated with remarkable disability, morbidity, and mortality. In patients with nonrevascularizable CLI, up to 40% may be subjected to limb amputations, and the mortality rate can reach up to 20% within 6 months. Diabetes mellitus is an important predisposing factor for peripheral artery disease and CLI. Investigators estimate that over 80% of patients with diabetic foot have peripheral artery disease. Amputations occur every 30 s as a result of diabetic foot. Eighty-five percent of these amputations are preventable.
Revascularization is the typical treatment for CLI, and it confers an improvement in distal limb perfusion. The provision of the optimum care for patients with CLI calls for a thorough understanding of the treatment strategies. The evolution of endovascular devices and technology during the last decade and the cost-effectiveness of endovascular treatment (EVT), as well as the higher perioperative morbidity of bypass surgery, have made EVT the first-line therapy for CLI.,,, Optimal medical therapy with statins in patients with CLI and those with vast atherosclerotic involvement lowers the rates of mortality and major adverse cardiac and cerebrovascular events (MACCEs) and increases the rate of amputation-free survival.,
However, the recurrence rate of CLI and limb loss after revascularization is relatively high, especially among patients with specific clinical backgrounds (e.g. end-stage renal disease, previous major amputations, and Rutherford Category VI) and anatomical features.,, The failure to adhere to optimal medical therapy after revascularization in the mid and long term by a large number of patients may increase the rate of MACCEs. A follow-up protocol is, therefore, essential to prevent adverse events in patients with CLI.
The objective of the present study is to evaluate the postprocedural and long-term outcomes of patients with CLI who undergo EVT according to multidisciplinary-based therapeutic and follow-up protocols. In addition, the predictors of procedural failure and adverse outcomes in the long term are investigated.
| Methods|| |
Study design and ethical considerations
The IRANCLI study is an observational single-center study that has been established as a registry.
All consecutive patients with CLI who meet the inclusion criteria at the peripheral and endovascular therapies division at Rajaie Cardiovascular, Medical, and Research Center have been assigned to the therapeutic protocol since May 2015 [Figure 1]. Our center is a tertiary-care hospital for cardiovascular diseases in Tehran, Iran. The study protocol was approved by the ethics committee of our center (Process number: 1394.44), and the design and report of the study adhere to the Strengthening the Reporting of Observational Studies in Epidemiology norms. This study follows international and national ethical regulations, and its design and conduct are in accordance with the Declaration of Helsinki. A written informed consent is obtained from all participants before enrollment. The vascular team of our center designed both the therapeutic and follow-up protocols. This team consists of 1 endocrinologist, 1 infectious disease specialist, 4 interventional cardiologists, 2 vascular surgeons, 1 orthopedist, and 1 plastic surgeon. The data of the included patients are registered during their hospital stay and each outpatient visit [Table 1]. All the eligible participants should sign the written informed consent before recruitment, and the participants have the right to leave the study at any time. The collected data and outcomes are confidential.
|Figure 1: Study Flow Chart. WIFI: Wound, Ischemia, and Foot Infection, TCPO: Transcutaneous pressure of oxygen, TBI: Toe-brachial index, ABI: Ankle brachial index, MACCE: Major adverse cardiovascular and cerebrovascular events, MRA: Magnetic resonance angiography, |
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The present study is conducted as a patient registry project, in which all patients who fulfill the inclusion criteria are registered. Consequently, there is no need for a power analysis to calculate the sample size. A time limit of 3 years, however, has been set for patient inclusion.
Patients between 18 and 85 years of age with CLI and severe claudication resistant to medical therapy who are considered eligible for revascularization without significant disability in their index limb are recruited to the study.
CLI is defined as the presence of ischemic or neuroischemic ulcers, tissue loss, and ischemic rest pain.
Significant ischemia indicating CLI is confirmed with arterial physiology tests – comprising ankle pressure (AP), toe pressure (TP), and transcutaneous pressure of oxygen (TCPO2). Cutoff values indicating critical ischemia via arterial physiology assessments are as follows:
- AP <70 mmHg and/or TP <50 or TCPO2 < 40 in patients with tissue loss and ulcers
- AP <50 mmHg and/or TP <30 or TCPO2 < 20 in patients with no tissue loss and ulcers.,,
The nonatherosclerotic causes of CLI such as Buerger's disease are not included.
Patients with primary major amputations before EVT due to severe infection (foot infection Class III according to the Wound, Ischemia, and Foot Infection [WIFI] classification) are excluded [Figure 1].
Patients with CLI are admitted, and the presence and severity of infection are assessed in cases with ulcers. Magnetic resonance imaging (MRI) and nuclear scintigraphy show the presence or absence of deep infection (e.g. osteomyelitis). In patients with significant infections (systemic involvement) that are life- or limb-threatening, urgent debridement and minor or major amputations constitute our approach before EVT. Ulcer-free patients with CLI undergo clinical and paraclinical assessments to verify significant ischemia as the cause of rest pain or claudication.
Data management and monitoring
The data of the recruited participants are registered into dedicated datasheets [Figure 2]. The data collectors are well-trained physicians who are able to evaluate patients clinically, according to the protocol. A well-trained physician in the present study is defined as a physician trained in vascular medicine with considerable experience in the diagnosis and endovascular management of patients with CLI. The IRANCLI Steering Committee (IRANCLISC) (including the principal investigators and data collectors) performs and directs the data collection. The collected data are anonymized for both the principal investigators and the Data Monitoring and Quality Center (DMQC) (Unit for Clinical Research and Biostatistics in Rajaie Cardiovascular, Medical, and Research Center), and each participant has an identification code. All the data are confidential, and if any participant declines to participate in the study after recruitment, the relevant information is destroyed confidentially. The data collection is carried out during index hospitalization and in each outpatient visit [Table 1]. The DMQC monitors, analyzes, and audits the imported data, outcomes, and variables. If there is a missing datum, outcome, or event, the Clinical Research Follow-up Committee (CRFC) makes direct phone calls to the patient. The CRFC has access to the contact information of each patient. The sources of missing data comprise patients' decision to discontinue participation, patients' delaying or missing scheduled visits, and mortality. Patients who miss the scheduled visits for more than 2 weeks are recommended to make the earliest possible outpatient visit. If mortality occurs, its cause is investigated and registered. The DMQC audits the data every 6 months. If there are any incomplete or contradictory data, the identification code is sent to the IRANCLISC for further reviews and corrections.
|Figure 2: Relationship between components of data management and monitoring system of IRANCLI study. CRFC: Clinical research follow up committee, DC: Data collector, DMQC: Data monitoring and quality center, IRANCLISC: IRANCLI steering committee, PI: Principal investigator|
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The data collectors gather and register demographic and background clinical data, wound status (according to the Texas University Wound Classification and WIFI classifications), presence of osteomyelitis (according to imaging results), angiographic data, procedural data (including procedural complications), hospital course, and follow-up data (including the presence or absence of rest pain or claudication, healing or worsening of the wound, recurrence of the wound, claudication, and rest pain).
Freedom from major adverse limb events (MALEs) is the primary end point. A MALE is defined as a major amputation or a major reintervention (surgical revascularization or thrombectomy). The different predictors of MALEs and the changes in their hazard rate are evaluated at 1-year and 3-year follow-ups. The secondary outcomes encompass amputation-free survival; limb salvage; and freedom from a composite of adverse events within the follow-up period, freedom from adverse cardiovascular events and limb amputations, and freedom from recurrent adverse limb events. The different predictors of the end points and the changes in the hazard rate of each end point are assessed at 1-year and 3-year follow-ups. Also evaluated are the rates of procedural success and complications, in addition to the predictors of unsuccessful procedures and 30 days' perioperative adverse events.
A successful EVT is defined as the success in establishing 1 straight-line flow to the foot without a significant complication that is limb- or life-threatening. Also, the treated vessel should have <30% stenosis after the procedure in the case of balloon angioplasty and <10% in the case of stent angioplasty [Table 2].
There are three main categories of patients: patients with ulcers, patients with rest pain, and patients with severe claudication. Ulcers are classified according to the WIFI classification. If there are any signs or paraclinical equivalents of systemic infection (i.e. foot infection Class III), the approach comprises debridement or amputations. Patients with major amputations are excluded at this point [Figure 1]. After debridement/minor amputations, the responsible physician reassesses the WIFI class. Those with critical ischemia undergo EVT. Patients without critical ischemia are excluded from the study at this stage.
In patients with rest pain and diabetes, ischemic, neuroischemic, or neuropathic causes of pain are investigated according to the characteristics of the pain, clinical findings, and arterial physiology assessment tests. These tests also form a part of the evaluation of other patients with rest pain or ulcers to rule out other nonischemic causes of rest pain.
In cases with severe ischemia-related claudication (Rutherford Category IV), the responsible physician prescribesa trial of medical treatment with statins, cilostazol, and a rehabilitation program for 4–6 weeks. If there is persistent claudication and severe ischemia after this period, the patient undergoes revascularization.
Arterial physiology assessment
The presence and severity of ischemia are evaluated with arterial physiology tests in all the participants. These tests comprised of the ankle-brachial index, the toe-brachial index, and TCPO2. Even in patients with arterial occlusions, there may be sufficient collaterals to maintain a functional distal flow. Therefore, these indices can determine the functional importance of an occlusion or stenosis in the arterial system. Nevertheless, the ankle-brachial index does not evaluate the severity of ischemia correctly in patients with diabetes mellitus or chronic kidney disease and in the elderly due to the higher rate and severity of vessel calcification. Thus, in these categories of patients and in those with an ankle-brachial index >1.4, the toe-brachial index and TCPO2 are more accurate in the determination of ischemia severity.
After the arterial physiology assessment tests, the participants undergo noninvasive imaging assessments. The modality of choice is ultrasonography, and computed tomography angiography or magnetic resonance angiography is reserved for those patients in whom ultrasonography fails to provide sufficient data regarding the anatomy. The choice between magnetic resonance angiography and computed tomography angiography is based on the patient's renal function. These imaging studies verify patients with an unsuitable anatomy for EVT and are essential for the preprocedural planning.
Imaging studies to evaluate osteomyelitis
Plain radiography is the easiest and most accessible modality to evaluate osteomyelitis or advanced infection (e.g. gas in the tissue). Periosteal thickening, osteopenia, cortical erosion, and new bone formation constitute the signs of osteomyelitis in plain radiography. Given the limited value of this modality and its inability to reveal the early phases of bone infection, other modalities such as MRI and nuclear scintigraphy are drawn upon to detect osteomyelitis in susceptible cases. Although nuclear scintigraphy has a good sensitivity, the presence of soft tissue infection (which is true for many diabetic foot ulcers) limits its specificity insofar as it may render the discrimination between osteomyelitis and soft tissue involvement difficult. MRI with gadolinium has the highest specificity and sensitivity (90% and 85%, respectively) and is able to find the signs of infection (bone-marrow changes in T1 and T2) only 3 days after infection initiation. In sum, a combination of imaging modalities is recommended to diagnose osteomyelitis, with plain radiograph being the first choice. If more accurate modality is needed, MRI is the best choice and nuclear imaging is reserved for contraindications to MRI.,
Digital subtraction angiography is used in the following conditions:
- Patients who are not eligible for computed tomography angiography or magnetic resonance angiography due to severe chronic kidney disease or acute kidney injury
- The presence of severe calcification within distal small vessels. Calcification is more prevalent in patients with end-stage renal disease or diabetes mellitus 
- Patients with previous arterial stenting. Stents can cause severe artifacts, making it difficult to have a good image of the arterial lumen.
In patients with renal dysfunction, CO2 is administered as the contrast agent.
Standard sheaths, catheters, wires, balloons (plain or drug-coated), stents, and other devices such as filter wires and atherectomy devices are utilized to carry out EVT according to the anatomy of the involved vessels. The treatment strategy is different in each segment and is as follows:
- Balloon stenting (including the covered endovascular reconstruction of aortic bifurcation technic or the simultaneous kissing stenting technic) with covered stents is applied for aortoiliac involvement 
- Balloon stenting with noncovered self-expanding stents is applied for iliofemoral involvement
- In femoropopliteal segment involvement, drug-coated balloons are the first choice, and stenting is reserved for those with flow-limiting dissections after ballooning (bail-out stenting).,, Given the significant vessel deformation during knee flexion, only a short length of the artery is covered with a highly flexible self-expandable stent in this segment – not least in the popliteal artery
- Plain balloon angioplasty is applied for below-the-knee involvement. In some cases with an isolated and short involvement of the proximal tibial vessels, coronary drug-eluting stents are placed as a bail-out technic.,
A minor amputation is defined as an amputation below the ankle joint. Its main goal is to control the infection and limit the progression of gangrene in the affected limb. The timing of amputations (pre-EVT or post-EVT procedures) depends on the severity of the infection. In patients with Class III infection (according to the WIFI classification) that present with the systemic signs and paraclinical findings of sepsis, amputations are considered before the procedure; otherwise, amputations are performed after EVT. The amputation technic involves removing all the infected and nonvital tissues. The surgeon evaluates the resultant surgical wound to find any changes in its size and healing process during hospitalization, especially following EVT. Casts, boots, and orthopedic shoes may be used accordingly. Cases with active infection (described as persistent erythema and tenderness around the ulcer, purulent discharge from the ulcer, and induration close to the ulcer) receive proper antibiotic therapy until the infection subsides.
Medical therapy after endovascular treatment
All the patients receive optimal medical treatment during hospitalization and at discharge, including dual antiplatelet therapy for 1 month (12 months in cases with the placement of drug-eluting stents) as well as lifelong statins and aspirin. Other medications such as antihypertensives are prescribed on the basis of other concomitant illnesses and standard guidelines.
The patients are followed up according to a fixed timetable at 1, 3, 6, 9, and 12 months and every 6 months after the 1st year. Active follow-up is applied for all the participants. The CRFC is responsible for the active follow-up program. If the patients postpone their scheduled date of visit for more than 2 weeks, the CRFC makes a phone call to inquire about the reason and schedule a visit as soon as possible. The CRFC also reminds the patients of the proper administration of their essential prescribed medications. Reintervention is carried out in patients with recurrent CLI during the follow-up.
The normal distribution of the variables is ascertained with the Kolmogorov–Smirnov normality test. According to the distribution and the type of the variables, standard statistical tests such as the Pearson Chi-square, the independent sample t-test, and one-way analysis of variance, or their nonparametric equivalents are conducted. The statistical significance point is set at 5% (P < 0.05). Regression models are applied for multivariable analyses. Survival analyses are performed with the Kaplan–Meier method and the Cox proportional hazard model or any other appropriate methods. The statistical tests are carried out with IBM SPSS Statistics (IBM Inc., Armonk, NY, USA) and Stata (StataCorp LLC, Texas, USA).
| Discussion|| |
CLI leads to significant morbidity and mortality if left untreated. Revascularization reduces the morbidity caused by limb loss in these patients. It has, however, been shown that revascularization – as a standalone strategy – cannot lessen mortality and morbidity due to cardiovascular causes., There is also a wide spectrum of presentations – from minimal symptoms to significant tissue loss, different concomitant illnesses, and different cardiovascular risk profiles – making a multidisciplinary approach essential for the achievement of optimum results in terms of wound healing, limb salvage, cardiovascular morbidity, and mortality.,
There is a paucity of data in our region on the epidemiologic and demographic characteristics, natural history, and prognosis of patients with CLI after EVT. The IRANCLI study was designed with a multidisciplinary-based approach to evaluate and follow up patients with CLI who undergo EVT. These data will help healthcare systems to formulate appropriate protocols for the treatment and follow-up of patients with CLI in keeping with regional lifestyles and facilities.
Other studies with long-term follow-ups have shown that the prognostic factors change over time,,,, which exacerbates the complexity of the situation when combined with the variety of CLI presentations and risk factors. The patency rate of the treated vessels is limited after either of the revascularization strategies (i.e. EVT or surgical), particularly in below-the-knee and femoropopliteal levels. As a result, the recurrence rate of CLI is considerable. This underscores both the significance of a meticulous follow-up protocol and the need for a follow-up system featuring active direct contact plans with patients.
To have an acceptable degree of generalizability, the IRANCLI study recruits all patients with CLI who fulfill the criteria for EVT. As the present study's inclusion and exclusion criteria have the fewest limitations, we expect a more desirable prospect of CLI burden and its consequences after EVT. On the other hand, the CRFC forges close contacts between the participants and the IRANCLISC with a view to diminishing the negative effects of delay/refusal for the follow-ups as much as possible. This active follow-up helps spot patients with recurrent CLI symptoms during their earlier stages. It is also possible to find patients with poor adherence to medical treatment and search for a resolution to overcome its causes. Furthermore, as the DMQC audits and analyzes the data every 6 months, it is feasible to make modifications to the protocol if there are unfavorable results during the follow-up.
There are several important limitations in the present study. The observational nature of the study increases the risk of selection bias, and the final result should be interpreted with more caution. In addition, our center is a high-volume referral tertiary center for patients from all over the country, but a single-center study cannot be an accurate estimate of the scope of the disease in a larger population. In our country, however, only a few centers systematically concentrate on managing patients with CLI and work dedicatedly on this subject. This nonsystematic approach might influence the reliability of the data coming from those centers, which explains why we opted to run the current investigation as a single-center registry.
| Conclusions|| |
The IRANCLI protocol is designed to reduce the rates of amputations and cardiovascular morbidity in patients with CLI by a center-approved multidisciplinary team. It features flexible multidisciplinary protocols and active follow-up systems with the aim of lowering the failure rate of the treatment and the number of missing patients. Furthermore, this study confers a more desirable prospect of the status of patients with CLI in the region.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]