Endovascular versus surgical treatment for acute limb ischemia: a systematic review and meta-analysis of clinical trials

Introduction

Acute limb ischemia (ALI) is a life and limb-threatening emergency that results from an abrupt decrease of blood flow to a limb, which threatens tissue viability in patients presenting within two weeks of the acute event. Severe, untreated cases can result in fatal metabolic derangements, limb amputation and death. The three main etiologies of ALI are distal embolization of athero- or thromboembolic material, vascular thrombosis of a high grade underlying lesion (of native vessel, bypass grafts or in-stent thrombosis) or secondary to a traumatic vascular injury (1-4).

The clinical presentation of ALI has the hallmark referred to as the 6 Ps (pallor, pain, pulseless, paralysis, paresthesia and poikilothermia). Clinically, ALI is classified as (I) viable (II) threatened and (III) non-viable tissue. This classification helps to direct therapy in terms of the urgency of intervention, appropriate pre-intervention evaluation and mode of intervention (3,5). While the treatment for non-viable ALI is amputation, treatment options for viable and threatened ALI include endovascular (ENDO) (i.e., intra-arterial thrombolysis, aspiration or rheolytic thrombectomy and/or angioplasty) or surgical (SURG) (i.e., thromboembolectomy, endarterectomy and/or bypass) revascularization.

Several studies have compared ENDO to SURG treatment strategies in this population. The goal of this study is to compare both approaches in regard with mortality and morbidity (limb amputation and recurrent ischemia) based on available evidence in the literature.

Methods

The aim of this meta-analysis was to compare outcomes associated with ENDO versus SURG in patients presenting with ALI (<2 weeks) between 1990 and 2016. The primary endpoints were all cause mortality and limb amputation at 1 month, 6 and 12 months. The secondary endpoint was recurrent ischemia at one year.

The study was performed following procedures recommended by the Cochrane collaboration (6) and is reported in accordance with the recommendations set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (7).

Information sources and search methods

A comprehensive literature search was conducted through the electronic databases MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for abstracts using various combinations of the terms: acute limb ischemia, SURG revascularization and ENDO revascularization.

Two reviewers (JO, TE) identified articles eligible for further review by performing a screen of abstracts and titles. If a study met the inclusion criteria, the manuscript was obtained and reviewed. In addition, bibliographic references of identified randomized clinical trials and review articles, in order to find randomized clinical trials not identified by the electronic searches, were evaluated.

Studies identification

The previously described data sources were searched for possible studies and the search was limited to the English-language literature. Original papers were included and the initial search identified 220 citations. One hundred and sixty citations were excluded by the identifying abstract/title. The final search identified 6 original papers that fulfilled the criteria for inclusion (Figure 1).

Figure 1 Data flow diagram depicting the procedure for study selection.

Data collection and extraction

Two independent reviewers (JO, TE) extracted data from the included studies by using pre-specified data elements. Data were abstracted on patient demographics and baseline characteristics, study design, sample size, duration of symptoms (<2 weeks), intervention type (ENDO vs. SURG) and type of outcome measures (primary outcomes: mortality and limb amputation as well as secondary outcomes: recurrent ischemia).

One review author extracted the data from included studies and a second author verified the extracted data. The number of events in each trial was extracted when available. Baseline characteristics and study description are reported (Table 1) (4,8-13).

Table 1 Summary of the studies and patient demographics
Full table

Risk of bias assessment

Methodological quality was defined as the control of bias assessed through the reported methods in each individual study using the Cochrane risk of bias tool (14) to assess quality of randomized trials. Newcastle-Ottawa Scale (NOS) (15) was used to assess the quality of observational studies. Two reviewers (JO, TE) independently assessed each study quality by examining risk of bias tool components. No evidence of publication bias was detected based on the symmetry of the funnel plot (Figure 2). There was possible performance bias due to non-blinded studies (Tables 2,3). Disagreements between the reviewers were resolved by discussion or arbitrated with a third coauthor (AA).

Figure 2 Funnel plot of studies show symmetry (Log risk ratio). RR, risk ratio.

Table 2 Study quality risk bias assessment for randomized clinical trials
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Table 3 Study quality risk bias assessment for cohort studies
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Statistical analysis and data synthesis

From the abstracted data, the risk ratio (RR) was calculated using the inverse variance method for each study outcome to allow for pooling of similar outcomes. The average effects for the outcomes and 95% confidence intervals (CIs) were obtained using a random effects model, as described by DerSimonian (14). We chose the random effects method as primary analysis because of its conservative summary estimate and incorporation between and within study variance.

To assess heterogeneity of treatment effect among trials, the I² statistic was used. The I² statistic represents the proportion of heterogeneity of treatment effect across trials that were not attributable to chance or random error. Hence, a value of 50% or more reflects significant heterogeneity that is due to real differences in study populations, protocols, interventions, and outcomes (14). Sensitivity analyses were performed to assess the effects of selected measures of study designs (i.e., randomized control trial versus observational studies) on pooled effect of ENDO vs. SURG. The influence was estimated by performing a subgroup analysis and test for subgroup differences. The analysis was repeated including randomized studies only and the results remained consistent.

The P value threshold for statistical significance was set at 0.05 for effect sizes. Analyses were conducted using features on RevMan version 5.3.5 (The Nordic Cochrane Center, Copenhagen, Denmark).

Results

A total of 1,773 patients was identified from a total of six studies. Five of those studies were randomized prospective studies, and the sixth study was an observational retrospective study.

Mortality

When comparing the two treatment options with respect to effect on mortality, no difference was found. This effect was observed at 1 month (RR for ENDO vs. SURG is 0.70; 95% CI, 0.33 to 1.50), 6 months (RR 1.12; CI, 0.78 to 1.61) or 12 months (RR 0.74; CI, 0.29 to 1.85) (Figure 3). A numerically higher mortality event rate in the SURG option was observed, but it did not reach statistical significance. This was seen at 12 months 96/918 ENDO vs. 165/855 SURG (Figure 3).

Figure 3 Analysis of mortality at 1 month, 6 and 12 months of patient undergoing ENDO vs. SURG demonstrated no statistical difference (4,8-13). ENDO, endovascular; SURG, surgical.

Amputation rate

When comparing the two treatment option with respect to amputation rate no difference was found. This effect was observed at 1 month (RR 0.75; CI, 0.40 to 1.42), 6 months (RR 0.87; CI, 0.52 to 1.48) or 12 months (RR 0.81; CI, 0.55 to 1.18) (Figure 4).

Figure 4 Analysis of limb amputation rate at 1 month, 6 and 12 months of patient undergoing ENDO vs. SURG demonstrated no statistically significant difference (4,8-13). ENDO, endovascular; SURG, surgical.

Secondary outcomes

Secondary outcome data was limited. Not difference between the two treatment options was observed (RR 1.12; CI, 0.75 to 1.67) (Figure 5)

Figure 5 Analysis of recurrent ischemia at 12 months in patients undergoing ENDO vs. SURG demonstrated no statistically significant difference (4,8-13). ENDO, endovascular; SURG, surgical.

Discussion

Presentation with ALI is considered a vascular emergency associated with major morbidity and mortality. It is estimated to occur in 1.5 cases/10,000 population per year, complicates 15–20% of chronic limb ischemia and has (3,4) a 30-day mortality rate close to 26% (16). Embolic occlusions can result from either atherosclerotic or thromboembolic debris and for this reason embolic ALI was excluded from some studies comparing local thrombolysis to SURG treatment (9-11).

Tissue plasminogen activator (tPA) is the most common thrombolytic agent used in treating ALI within 1–2 days of presentation (3,4). Intra-arterial thrombolytic therapy is a less invasive approach when compared to SURG revascularization and can be followed by an ENDO or simpler open procedure if required (9-11). However uncertainty exists regarding the optimal revascularization approach (ENDO vs. SURG) as the first line treatment. The 2012 American College of Chest Physicians suggests reperfusion therapy (SURG or ENDO) over no reperfusion therapy and recommends SURG over ENDO for both thrombotic and embolic ALI (17).

Previous studies in the early nineties on treatment for ALI showed ENDO to have comparable results to SURG in terms of mortality, limb amputation and recurrent ischemia at up to one year of follow-up. These results were confirmed by subsequent and more recent studies. These studies also showed that ENDO was associated with worse outcomes when used for treatment of ALI secondary to prosthetic bypass graft occlusion or for treatment of chronic limb ischemia (symptoms of >2 weeks) (9-12,17-20).

This analysis shows no significant difference between the two treatment options in terms of mortality at 1 month, 6 and 12 months, amputation rates or recurrent ischemia at 12 months of follow-up. This study increases the sample size and confirms the equipoise that exists with either an early ENDO or SURG revascularization strategy for ALI. With the lower morbidity that is associated with the ENDO approach, the data presented here support the concept that an ENDO first approach for ALI is a reasonable first line option.

Limitations

This study has several limitations. Although the majority of studies included were randomized, and prospective, one retrospective study was included. All of these studies recruited patients with different co-morbidities and risk factors so heterogeneity as seen in any meta-analysis is a factor to consider.

There was also heterogeneity between the included studies with respect to SURG procedures performed, type and dose of thrombolytic used and type of target vessel (native vs. bypass graft). Finally, there was a lack of uniform reporting of the severity assessment of ALI, which could have an implication on outcomes. The most recent study by Taha and colleagues (12) was the only study that used Rutherford classification of ALI and its results suggested that ENDO might be the preferred first line of treatment for Rutherford 2 native artery/stent failure ALI while SURG might be preferred for bypass graft ALI (12).

The recent advances and improvements in catheter-directed therapy is a factor not well accounted for in this analysis as the majority of the included studies were older and prior to the contemporary ENDO techniques. This is likely to have biased the results in favor of the SURG approach.

Conclusions

In conclusion, this study shows that an ENDO first approach would result in no significant difference versus a SURG approach in terms of mortality and recurrent ischemia and may reduce short-term limb amputation rates for patients with ALI Further randomized trials are required to provide further confirmation of these findings.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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