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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 87-94

Patients with critical limb ischemia (CLI) not suitable for revascularization: the “dark side” of CLI


Department of Vascular Surgery, Unit of Angiology, Ospedale San Martino Belluno, AULSS 1 Dolomiti, Belluno, Italy

Date of Submission08-Apr-2021
Date of Decision01-May-2021
Date of Acceptance03-May-2021
Date of Web Publication20-Jul-2021

Correspondence Address:
Dr. Romeo Martini
Unit of Angiology, Ospedale San Martino Belluno, AULSS 1 Dolomiti, Belluno
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2589-9686.321924

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  Abstract 


Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease (PAD). Its prognosis is poor, with high rates of limb amputation and cardiovascular mortality. The international guidelines consider limb revascularization as the first line of the treatment strategy for CLI. However, despite the progress of revascularization techniques, many patients with CLI are still considered not suitable for these procedures and treated with conservative limb treatments. We have consulted the most important guidelines on PAD and CLI published over the past two decades focusing on the epidemiology, treatment, and outcomes of CLI patients not suitable for revascularization. Our review shows that only the TASC guidelines report 25% of CLI patients conservatively treated. Regarding the treatments, all the guidelines agree that the conservative treatment is based on the best medical management of cardiovascular risk factors associated with pain drugs and wound management. Other treatments such as prostanoids, spinal cord stimulation, vasodilators, or angiogenic therapies have shown uncertain positive outcomes in reducing limb amputation and mortality. In conclusion, this work outlines the scarce consideration that the guidelines have had about these patients over the past two decades. However, this review tries to draw the main novelties and possible future treatments for the better management of this group of patients still resident in the “dark side” of the CLI.

Keywords: Conservative treatment, critical limb ischemia, critical limb threatening ischemia


How to cite this article:
Martini R, Ghirardini F. Patients with critical limb ischemia (CLI) not suitable for revascularization: the “dark side” of CLI. Vasc Invest Ther 2021;4:87-94

How to cite this URL:
Martini R, Ghirardini F. Patients with critical limb ischemia (CLI) not suitable for revascularization: the “dark side” of CLI. Vasc Invest Ther [serial online] 2021 [cited 2021 Dec 6];4:87-94. Available from: https://www.vitonline.org/text.asp?2021/4/3/87/321924




  Introduction Top


Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease (PAD), clinically defined as limb rest pain with or without foot or leg skin ulcers or gangrene.[1]

CLI is associated with macro and microcirculatory disorders[2] with high limb amputation rates and cardiovascular mortality.[3]

The international guidelines consider that limb revascularization is the first-choice treatment for CLI patients.[4],[5] However, in the past two decades, despite the progress of the revascularization procedures, particularly of endovascular techniques, many patients with CLI are still considered not suitable for revascularization.[5]

These patients are a heterogeneous group, often elderly and frail subjects, with multiple comorbidity factors such as diabetes, chronic kidney disease, and chronic pulmonary disease. Frequently, they have previously failed limb revascularization procedures with a poor leg-pedal arterial run-off, but their limb is still viable and not indicated for primary amputation.[6] Wounds and conservative limb medical therapy consisting of pain control wound treatments with the best cardiovascular risk management is their therapeutic option in real life.[7]

Prostanoids,[8],[9], [10,[11] spinal cord stimulation,[12] intermittent pneumatic compression,[13],[14],[15],[16],[17] and angiogenic treatment[18],[19],[20] over the past two decades have been utilized to improve the CLI limb and patients' survival. However, the outcomes achieved with these treatments did not show significant improvements. Therefore, over the past two decades, the guidelines have gradually expressed weak recommendations on their use, leaving these patients orphans of specific treatments.[1],[3],[4],[5],[7],[10],[21],[22],[23],[24],[25]

In contrast with this scenario, some authors have recently hypothesized that the new cardiovascular management strategy as the statin treatment changes may have determined better limb amputation and mortality rates over the past 10 years.[26],[27]

Moreover, to these hopeful suggestions, the reduction of major amputations and mortality observed in PAD patients treated with a low dose of direct oral anticoagulant and with inhibitors of proprotein convertase subtilisin/kexin type could also positively affect CLI patients.[28],[29]

Therefore, there are now compelling arguments for reviewing some issues regarding the patients and drawing new suggestions about their treatments. This paper hopes to help stimulate future investigation about these neglected patients' residents in the “dark side” of the CLI.

Epidemiology of patients with critical limb ischemia not suitable for revascularization

There is scarce evidence in the most consulted guidelines on PAD about the epidemiology of patients with CLI not suitable for revascularization.

In 2000 and 2007, the TASCs reported that 50% of patients at their first CLI episode had been treated with revascularization procedures. Of the remaining patients considered unsuitable for revascularization, 25% were treated with primary amputations and 25% with conservative limb treatment, consisting basically in medical therapy.[1],[10]

In the past two decades, no other guidelines have reported the rate of CLI patients considered not suitable for revascularization treated conservatively. To have some evidence, we have consulted the literature of the past two decades.

The revascularization rate has significantly fluctuated from 80%, in some single-center study with a more aggressive approach,[30],[31],[32] to lower than 60% showed in some multicenter trials.[33],[34],[35],[36] representing the average of CLI patient conservative care likely.

Moreover, in 2013, in a Medicare population data study, Baser reported that, in the United States, revascularization was offered only to 34% of CLI patients at their first episode. He concluded that it was reasonable to guess that more than 50% of patients were provided with medical treatment in real life.[37]

Biancari, in 2014, in 2144 legs with CLI, reported a 20% rate of conservative treatment.[26]

Moreover, in 2018, analyzing the CLI treatment from 1993 to 2015, our previous review showed that 18% of 5000 patients at their first episode were still conservatively treated.

Simultaneously, the revascularization grew from 50% to 72%, and more significantly, the endovascular procedures from 2% to 77%.[38]

Therefore, from these data, it is reasonable to guess that about 20% of CLI patients are still treated with medical therapy because considered not suitable for revascularization. , Hence, almost one in five of the total CLI population.

Clinical features of patients with critical limb ischemia not suitable for revascularization

Patients with CLI present a broad spectrum of clinical signs, hemodynamic conditions, and anatomic diseases. These patients have high comorbidity and a very high risk of limb amputation and mortality.[6] Data from the literature show that 23% required major amputation after 2 years, and 31.6% had died, primarily of cardiovascular disease.[39]

In these patients, the age-adjusted prevalence of diabetes, ischemic stroke, heart failure, and atrial fibrillation is doubled and tripled in renal failure. One in five has a cancer diagnosis.[40] However, other conditions such as the patients with no prospect of mobilization, limited life expectancy, or failing to consent to an invasive treatment have been reported. Furthermore, the TASC II C/D lesions have been among the criteria of choice for conservative treatment.[41],[42]

The most frequent motivations for conservative treatment are the high comorbidity associated with poor leg pedal arterial run-off with a not limb or life-threatening skin lesion.[34],[39]

Treatments for critical limb ischemia not suitable for revascularization over the past 20 years

Over the past two decades, the guidelines on PAD suggested performing conservative treatment for patients with CLI not suitable for revascularization, with the best medical therapy for atherosclerosis risk factors, comorbidities, pain and wounds.[1],[3],[4],[5],[7],[10],[21],[22],[23],[24],[25]

Other treatments such as prostanoids,[8],[9],[10],[11] vasodilators,[1],[3],[10] heparin,[43] spinal cord stimulation,[12] hyperbaric oxygen therapy,[1],[7] intermittent pneumatic compression,[13],[14],[15],[16],[17] and more recently, angiogenic therapies have raised some concerns about their use to improve the patients' outcomes.[18],[19],[20]

The efficacy of all these treatments has been discussed in the literature causing controversial debate not always in agreement over the past two decades, as reported in [Table 1].
Table 1: Evidenceinguidelinefrom2000to2020;ofprostanoids,vasoactivedrugs,hyperbaricoxygentherapy,spinalcordstimulation,intermittentpneumaticcompression,angiogenictreatments

Click here to view


The use of prostanoids has been one of the most argued issues.

Prostanoids are a group of molecules inhibiting the activation and adhesion of platelets and leukocytes. This family includes prostaglandin E1 (PGE 1), prostacyclin (PGI 2), epoprostenol (PG12), lipo-ecraprost, taprostene, and iloprost.

These drugs promote vasodilation and vascular endothelial cytoprotection through antithrombotic and profibrinolytic actions, which are deemed favorable for CLI.[8],[9],[10],[11]

After the enthusiastic results in the '90s,[8],[9] concerns about their effectiveness on CLI have been raised in the years later.[44] Consequently, the guidelines have weakened the level of their recommendations and in some cases, have defined them as ineffective.[7]

However, recently, some new observations have highlighted a possible role of prostanoids in CLI again.

In 2012, our previous retrospective observation in 99 elderly patients with not reconstructable CLI, 88% received prostanoids infusions, 14% low-molecular-weight heparin or oral anticoagulants, 3% spinal cord stimulation, 17% hyperbaric oxygen therapy, and 69% wound treatment. At 24 months, 13% of patients underwent toe or other foot-sparing amputations, 9.3% had a major amputation, and 23.2% died.[45]

Vietto et al., in a 2018 Cochrane review, found that prostanoids reduced rest pain and promoted ulcer healing in CLI patients with moderate-quality evidence.[46]

The global vascular and European Society of Vascular Medicine guidelines in 2019 have suggested their use again, albeit in selected CLI patients not suitable for revascularization.[4],[5]

Meini et al. in 2020 reported that the coarse efficacy claimed about prostanoids in the past was achieved by analyzing the whole group of prostanoids. Iloprost alone has shown results in reducing pain and improving wound healing in CLI.[47]

Nevertheless, besides these new observations about a revival of prostanoids in CLI, recent reviews have shown a generally better outcome of the conservative treatment in CLI over the past decade. Van Reijen et al. this year observed a 12-month major amputation rate between 22% and 27% and a mortality of 18%–22%.[27] According to these authors, these better outcomes might be due to cardiovascular risk management in the past 20 years and in particular, by more aggressive statin therapy in PAD, as some other authors reported.[27],[48],[49]

Indeed, the heart protection study published in 2002 showed the positive effects of blood lipid-lowering on PAD patients. This study showed that 40 mg daily of simvastatin reduced 25% of the cardiovascular events, suggesting that statin therapy reduced the inflammation burden of patients with PAD.[50]

Years later, the JUPITER study confirmed this suggestion, revealing that rosuvastatin 20 mg daily reduce up to 54% of the incidence of myocardial infarctions, to 48% the strokes and 46% the arterial revascularization in those patients with a low or high level of low-density lipoprotein (LDL) cholesterol but with a high level of protein C.[51]

The following study reinforced the concept demonstrating reduced major amputation and mortality rates among patients with stable PAD receiving high-dose statins.[48]

Now, statin treatment is recommended by the most recent international guideline for all PAD patients with a recommendation I A[4],[5]

Moreover, the positive statin effects on PAD outcomes also, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), have shown a beneficial effect in reducing limb amputation rates.[52]

ACE and ARBs are well known to reduce the risk of cardiovascular major events and mortality in patients with PAD.

Khan et al. recently reported that these drugs had significantly improved limb survival and amputation-free survival in CLI at 5 years, reaching 88% and 77.3%, respectively.[52]

Besides the positive outcomes on the cardiovascular system by lowering blood pressure, ACE and ARBs inhibitors have a pleiotropic protective action on arterial vessels.

In particular, they stabilize the atherosclerotic plaques, improve endothelial function, and enhance angiogenesis. These effects seem to be of specific interest for microcirculation and consequently, might determine the limb's fate in CLI patients.[53]

Therefore, the reported observations highlighting the recent reduction of amputations and mortality observed in CLI patients treated conservatively might have been achieved with more aggressive management of cardiovascular risk factors than other treatments.

New treatments for critical limb ischemia?

Besides the recent reassessment of the use of prostanoids to reduce pain and improve healing of skin ulcerations in CLI, the above suggested recent observations may indicate new strategies of treatment for CLI.

The further cardiovascular outcomes research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) study showed that evolocumab, a PCSK9 inhibitor reduced major cardiovascular events by 27% and in particular, the acute limb ischemia by 44%, and limb amputation of 70% in PAD patients already receiving statin therapy.[29]

The data coming from the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) study showed that, in PAD patients treated with low-dose rivaroxaban plus aspirin, the cardiovascular death, myocardial infarction, or stroke was reduced by 30% less than aspirin alone, major adverse limb events were also reduced by 55% and major amputations alone by 70%.[28],[54]

The vascular outcome study of ASA and rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD) study[51] confirmed the favorable outcomes of the COMPASS study. This study found a reduction of 20% in coronary heart disease death, myocardial infarction, ischemic stroke, and acute limb ischemia.[55]

The results provided by the FOURIER, COMPASS, and VOYAGER PAD studies have not yet been tested on CLI patients and in particular, on those deemed not suitable for revascularization.

However, they provide many arguments to presume positive effects in these patients more affected by inflammation or conditions that may lead to atherothrombosis.

The reduction of LDL-cholesterol associated with better control of the atherothrombotic process with low-dose rivaroxaban plus aspirin could reduce the risk of adverse cardiovascular and limb events in CLI patients not suitable for arterial reopening procedures.[28],[55]

Consequently, despite the higher major bleeding expected,[54],[55],[56] these new treatments could represent an absolute novelty for CLI in terms of net clinical benefit.

Final comment

This work highlights how in the past 20 years, PAD guidelines have not considered the CLI patients not suitable for revascularization. However, despite the progress of revascularization techniques, their percentage has remained high. About 20% of the entire CLI patient population is treated with conservative therapy in their first episode, even today.

These patients with CLI not suitable for revascularization remain neglected by the literature that seems more committed to following the progress of revascularization techniques.

This discrepancy highlights an awareness problem that affects the entire population of CLI patients.

Even today, recent observations confirm the disparities in PAD awareness in European countries.[56] Reduced awareness in the PAD is an old and severe problem, but it becomes more so in the CLI.

Although the PARTNERS study in 2001 underlined the lack of early diagnosis of PAD,[57] Goodney, in 2013, observed that many patients do not even receive angiography in the year before major limb amputation.[58] About 50% of patients presenting with CLI have no previous PAD diagnosis.[59],[60] All these data suggest that an unknown PAD could often lead to limb amputation after skin not healing posttraumatic ulcers in an elderly asymptomatic patient.

Early diagnosis of CLI becomes then essential for a good outcome.[61]

Another aspect that limits the understanding of the treatment efficacy used for patients with not revascularizable CLI is the outcome assessment.

CLI patients not suitable for revascularization may be need focused outcomes and in particular, those patients conservatively treated. Their outcomes should be related to their real-life expectancy than to the amputation or mortality rates reported in many studies regarding not frail CLI patients.

Many of these patients treated conservatively have limited deambulatory capacity and expectancy of life, and sometimes, the relief of pain could significantly improve their quality of life.

In conclusion, the literature should increase attention to not revascularizable patients to improve its incomplete CLI picture. Improve treatment and address unmet needs could benefit this vulnerable population.[62]

We can finally underline the compelling need to improve CLI patients' knowledge not suitable for revascularization to enhance the understanding of CLI.

However, these patients remain neglected by literature, orphan of specific management, and still resident in the dark side of the CLI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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