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Submaximal angioplasty in the treatment of patients with symptomatic ICAD: a systematic review and meta-analysis
  1. Seyed Mohammad Seyedsaadat1,
  2. Yagiz Ugur Yolcu2,
  3. Ain Neuhaus3,
  4. Asim Rizvi1,
  5. Muayad Alzuabi4,
  6. Mohammad H Murad5,
  7. Waleed Brinjikji6,
  8. Mohamad Bydon2,
  9. David F Kallmes7
  1. 1 Department of Radiology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
  2. 2 Department of Neurologic Surgery, Mayo Clinic Minnesota, Rochester, Minnesota, USA
  3. 3 Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  4. 4 Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
  5. 5 Center for Science of Healthcare Delivery, Mayo Clinic, Rochester, Minnesota, USA
  6. 6 Mayo Clinic Minnesota, Rochester, Minnesota, USA
  7. 7 Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Yagiz Ugur Yolcu, Department of Neurologic Surgery, Mayo Clinic Minnesota, Rochester, MN 55902, USA; yolcu.yagiz{at}mayo.edu

Abstract

Introduction Management approaches for intracranial atherosclerosis include medical, surgical, or endovascular treatment. Among endovascular treatments, recent studies have stated that submaximal angioplasty (SA) may offer considerable benefits and be a promising alternative to aggressive medical therapyand/or stenting in the treatment of intracranial atherosclerotic disease (ICAD).

Objective To investigate the rates of periprocedural and long-term cerebrovascular accidents, mortality, and restenosis in patients with symptomatic ICAD who were treated with SA.

Methods An electronic database search was performed for relevant studies that reported clinical outcomes of patients with ICAD following SA. Outcomes of interest were incidence of transient ischemic attack, intracerebral hemorrhage, stroke, and mortality in the periprocedural period and at 1 year. The periprocedural period was defined as the time from SA until 30 days after the procedure. Technical success and restenosis rates after the procedure were also analyzed.

Results A total of 19 studies with 777 patients were identified. The technical success rate was 93% (95% CI 85% to 98%). The incidence of 30-day and 1-year stroke (all types) was 3% (95% CI 1% to 5%) and 5% (95% CI 4% to 8%), respectively. Thirty-day and 1-year mortality was found to be 1% (95% CI 0% to 2%) and 2% (95% CI 0% to 4%), respectively. The combined incidence of stroke or death was 5% (95% CI 3% to 8%) at 30 days, and 9% (95% CI 7% to 12%) at 1 year.

Conclusion The findings suggest that SA might be a promising alternative treatment in the treatment of symptomatic ICAD due to its favorable technical profile, periprocedural safety, and long-term efficacy. A randomized clinical trial is warranted to compare the safety and efficacy of SA with 'gold standard' medical treatment.

  • angioplasty, balloon
  • endovascular procedures
  • intracranial arteriosclerosis
  • stroke
  • treatment outcome

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Introduction

Intracranial atherosclerotic disease (ICAD) is the underlying cause of ischemic strokes in 5–10% of cases. The estimated annual stroke rate is between 3.1% and 8.1% and annual all-cause mortality for ICAD is between 7.8% and 17.2%.1 2 Treatment for ICAD is divided into medical and endovascular procedures, including angioplasty with stent placement or primary intracranial balloon angioplasty alone.3 4 A prior meta-analysis by Siddiq et al showed lower rates of 1-year stroke/death and restenosis in patients with symptomatic ICAD after treatment with angioplasty plus stent placement than with angioplasty alone.1 However, the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study5 showed a higher incidence of perioperative complications, 30-day stroke or mortality rate (14.7%), and 1-year stroke or mortality rate (23.4%) after stenting plus medical therapy than with aggressive medical therapy (AMT) alone (30-day stroke/death 5.8%). Although the SAMMPRIS study demonstrated a lower incidence of stroke with medical therapy alone, 12% of patients in the AMT arm developed recurrent stroke or death within 1 year, highlighting an unmet need for further treatment options. Indeed, if the perioperative complications are minimized, it is possible that endovascular treatments may still be useful in symptomatic ICAD.

Symptomatic intracranial atherosclerosis can result in a variety of clinical syndromes, including hypoperfusion, embolic phenomenon due to plaque rupture, and occlusion of perforators from the plaque itself. Submaximal angioplasty (SA) is an effective tool for the treatment of patients with hypoperfusion syndrome. By marginally increasing the diameter of the affected blood vessel, blood flow is markedly increased, thus alleviating the patient's hypoperfusion-type symptoms. This occurs because blood flow is proportional to the fourth power of the radius. Thus, even a 10% increase in diameter can result in a 46% increase in blood flow while a 20% increase in diameter will result in a greater than 200% increase in blood flow. The addition of maximum medical therapy to SA can then help to promote plaque remodeling and sustain the increase in lumen.3 4 6–8

SA is thought to be safer than conventional angioplasty or angioplasty and stenting for a number of reasons, including decreased procedural complexity, decreased risk of local perforator occlusion, and decreased cracking of the plaque, resulting in lower rates of distal embolization. Decreased plaque cracking is due to the technique of slow balloon inflation by 1 atm/min when performing SA. Therefore, we performed this systematic review and meta-analysis to evaluate the rates of technical success, periprocedural complications, follow-up restenosis, and long-term clinical outcomes of patients with symptomatic ICAD who were treated with SA, and to compare the findings with results from previous reports.

Methods

Data sources and search strategies

This study is reported in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. A comprehensive search of several databases from 1980 to January 29, 2019, for articles in English, was conducted. The databases included Ovid Medline Epub ahead of print, Ovid Medline in-process and other non-indexed citations, Ovid Medline, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search strategy was designed and conducted by an experienced librarian with input from the study’s principal investigator. Controlled vocabulary supplemented with keywords was used to search for angioplasty for patients with symptomatic intracranial stenosis.

Study eligibility

Symptomatic ICAD was defined as ≥50% stenosis of the symptomatic artery based on preoperative angiogram. SA was defined as any procedure that involves a balloon angioplasty without dilatation to the normal size of the vessel. Figure 1 shows a schematic representation of SA and a comparison with primary angioplasty. A case example of SA is also provided in figure 2. Human studies that reported the technical success, and clinical outcomes of patients with symptomatic ICAD, were included. When multiple reports were available for the same or overlapping population, the most recently published reports containing complete demographic and clinical data of the patients with ICAD were included. The following papers were excluded: (1) non-original (ie, review articles, case reports, technical notes, conference papers, editorial comments, and letters); (2) non-relevant to the topic; (3) non-English language; (4) with fewer than 10 patients; (5) with endovascular intervention for etiologies other than ICAD, such as aneurysm repair, acute stroke, vasculitis, and arterial dissection; (6) with attempted angioplasty in more than one artery and/or following failed stenting.

Figure 1

Schematic representation of the different performance of submaximal angioplasty versus primary angioplasty.

Figure 2

Example of submaximal angioplasty. Patient with history of multiple episodes of amaurosis fugax in the left eye and occasional transient episodes of right-hand weakness. (A) CT perfusion TMAX map shows hypoperfusion in the left hemisphere. (B) Pre-angioplasty left internal carotid artery (ICA) angiogram shows a severe, 80% stenosis of the proximal left cavernous ICA. (C) The patient was treated balloon angioplasty using a Rebel Monorail 3 mm x 8 mm coronary balloon. The degree of stenosis is now reduced to 50%. The patient had no complications and at follow-up has had no ischemic events.

Data collection and outcome variables

Two authors (SMS and AR) independently screened all studies for eligible papers by reviewing titles and abstracts. Three authors (SMS, AN, and YUY) independently performed full-text review of eligible papers and extracted data from included articles. After discussion between data extractors, consensus was reached for all cases. The following data were collected: title of the study, first author and publication year, patient demographics, study design, total number of patients, comorbidities, smoking status, antiplatelet use, pretreatment stenosis, balloon name, site of ICAD (anterior vs posterior circulation as well as specific vessels), follow-up duration, and clinical outcomes including incidence of transient ischemic attack (TIA), intracerebral hemorrhage (ICH), stroke and mortality in the periprocedural period and at 1 year. The periprocedural period was defined as the time from treatment with SA until 30 days after the procedure.

Risk of bias assessment

To determine the quality of studies included in this systematic review and meta-analysis, the modified Newcastle Ottawa Scale was used to assess the risk of bias in the studies.9 Using this scale, we evaluated each study based on eight criteria and divided them into three categories: (1) selection of the study groups; (2) comparability of the study groups; and (3) ascertainment of the outcome of interest. Risk of bias was assessed as high, low, or unclear by an independent author (MA).

Statistical analysis

Event rates and 95% confidence intervals (95% CIs) were estimated for each study outcome. Event rates were pooled across studies using random effects meta-analysis.10 Heterogeneity across studies was assessed using the I2 statistic.11 A subgroup analysis was performed to compare outcomes between anterior and posterior circulation ICAD and between patients with ≥50 or ≥70 stenosis. Publication bias across the studies was evaluated visually using funnel plots, and tested formally using the Egger method. The analysis was performed using STATA version 14 (StataCorp LP, College Station, Texas, USA).

Results

Literature search

The initial systematic literature search identified 591 articles. After excluding two duplicates, two authors (SMS and AR) independently screened the 589 unique articles by title and abstract. Of those, 218 review articles and conference abstracts, 14 papers with fewer than 10 patients, and 258 papers irrelevant to the topic of interest were excluded. The full text of the remaining 99 papers was retrieved for detailed review. Of these, 80 were removed because of failure to provide outcomes or because they included overlapping patient populations (eg, submaximal angioplasty and stenting combined). In total, 19 articles consisting of 777 unique patients treated with SA alone were included. Online supplementary file 1 shows the PRISMA flow diagram of the process of screening and selection of the eligible studies.

Study and patient characteristics

Of the 19 eligible studies, only two were multicenter.3 4 6 8 12–26 Fourteen (73.7%) studies were retrospective (702 patients) and 5 (26.3%) were prospective (75 patients) (table 1). The mean follow-up period ranged from 0.8 to 5.3 years with a mean of 2.62 years. The mean age of subjects was 60.7 years (range 48.7 to 67.8 years), and the majority of patients were male (492; 67.7%). Of the total number of intracranial stenotic arteries, 491 were located in the anterior circulation and 288 in the posterior circulation. Pretreatment and post-treatment stenosis rates varied from 76% to 90% (mean 81.6%), and 20% to 55% (mean 35.2%), respectively. Twelve studies included patients with symptomatic ICAD with ≥70% intracranial artery stenosis while only six studies included cases with ≥50% stenosis. Information on pretreatment stenosis percentage was missing in one study. A detailed description of the study and patient characteristics is provided in table 1.

Table 1

Studies and patients baseline characteristics

Risk of bias

The risk of bias was low in 11 studies, moderate in seven studies, and high in one study (online supplementary file 2).

Periprocedural complications

Overall, periprocedural complications following SA were reported in 24.6% of patients, including symptomatic and asymptomatic arterial dissection, transient neurological dysfunction during the procedure, and puncture site hematoma.

Short- and long-term clinical outcomes

Incidence of TIA, ICH/subarachnoid hemorrhage (SAH), stroke, and mortality at 30 days

As summarized in figure 3, among 19 studies (777 patients) that reported periprocedural clinical outcomes following SA, the overall incidences of 30-day TIA (among 15 studies) and ischemic stroke were ~0% (95% CI 0% to 1%) and 2% (95% CI 1% to 4%), respectively. Periprocedural ICH/SAH occurred in ~0% (95% CI 0% to 1%) of patients. Mortality rate at 30 days following SA was 1% (95% CI 0% to 2%).

Figure 3

Forest plots demonstrating 30-day outcomes as rates of (A) transient ischemic attack (TIA); (B) ischemic stroke; (C) intracerebral hemorrhage (ICH)/subarachnoid hemorrhage (SAH); (D) overall stroke; (E) death; (F) stroke or death.

Incidence of TIA, ICH/SAH, stroke, and mortality at 1 year

Among 19 studies (777 patients; figure 3), the overall incidence of all types of stroke at 1 year was 4% (95% CI 3% to 6%). Mortality rate at 1 year following SA was 2% (95% CI 0% to 4%). Figure 3 and online supplementary file 3 show a forest plot of the 30-day and 1-year incidence of stroke and/or death across included studies.

Angiographic outcomes (technical success and follow-up restenosis rates)

As shown in online supplementary file 4, the overall rate of technical success after submaximal angioplasty was 93% (95% CI 85% to 98%). Among a total of 15 studies for which follow-up angiographic reporting was available, the overall restenosis (defined by any symptomatic or asymptomatic stenosis) rate was 20% (95% CI 12% to 30%). A comparison of results for the outcomes of interest with results in recent publications is presented in online supplementary file 5.

Subgroup analysis of 1-year outcomes

The incidence of stroke/death was lower in studies with a higher degree of baseline artery stenosis (6.7% in ≥70% stenosis vs 10.8% in ≥50% stenosis), higher in prospective studies (10.6% vs 8.1%), and higher in patients with anterior circulation ICAD (16.9% vs 10.3%).

Discussion

This meta-analysis comprising 19 studies and 777 patients indicates the favorable safety and efficacy of SA in patients with symptomatic ICAD. In comparison with the findings of SAMMPRIS and other trials for stenting and medical treatment, SA was associated with lower rates of 30-day and 1-year cerebrovascular events and death compared with those who underwent stenting and angioplasty, and had comparable results to the medical treatment arm.

Although AMT is the preferred treatment in patients with symptomatic ICAD, those with poor anterograde circulation combined with severe stenosis are at high risk for future brain ischemic events and of becoming refractory to medical treatment.8 The primary drawbacks of alternative treatments, including stenting and primary angioplasty alone, are challenging navigation through tortuous arteries and iatrogenic arterial dissection.8 Moreover, stenting is commonly associated with arterial wall injury and intimal hyperplasia, which might lead to distal embolization and consequent periprocedural perforator stroke, as seen in SAMMPRIS.26 Complete flow restoration following primary angioplasty is also associated with increased risk of dissection and ICH due to hyperperfusion syndrome, caused by an abrupt increase in blood flow and slow recovery of the vessel lumen.8 Therefore, evaluating an alternative solution such as SA is warranted to achieve efficacy greater than AMT, while minimizing the safety concerns associated with interventional procedures to date.

Most available studies of SA have reported promising results following SA treatment of patients with ICAD for the restenosis rate, perioperative complications, and long-term cerebrovascular disease and functional outcome. In the largest cohort of 129 patients with ICAD who underwent SA, a technical success rate of 97%, periprocedural ischemic stroke rate of 5.4%, and 30-day to 1-year ischemic stroke rate of 2.3% were observed by Peng et al.26 The results of our meta-analysis provide further robust and systematic evidence for the importance of SA in reducing the rates of perioperative complications and long-term cerebrovascular events in patients with ICAD. Our results extend the findings of smaller studies, which could not generalize their results owing to their single-center nature, small scale, or retrospective design.

Although inconclusive, it seems likely that the lower incidence of perioperative complications, cerebrovascular events, and mortality in patients who were treated with SA rather than stenting and/or angioplasty alone can be attributed to its partial but adequate augmentation of blood flow to the brain, which may decrease the risk of hyperperfusion-related intracerebral hemorrhage,8 while retaining beneficial effects in patients with distal hypoperfusion at risk for recurrent stroke.26 Another benefit of SA is its ability to limit vessel wall damage, which possibly reduces the risk of plaque trauma, dissection or perforation, distal embolization, and perforator vessel occlusion. The lower rate of cerebrovascular events and mortality following SA can also be explained by the reduced restenosis rate at follow-up.

While SAMMPRIS excluded patients with intracranial artery stenosis of 50–69%, our subgroup analysis showed a lower incidence of cerebrovascular accidents/death in studies that included patients with intracerebral artery (ICA) stenosis of ≥70% than in those with ICA stenosis ≥50%. This interesting finding might indicate an even higher efficacy of SA in high-grade ICA stenosis (≥70%) compared with AMT. One possible reason for the higher efficacy of SA in our study compared with the medical treatment arm in SAMMPRIS could be the uncertainty of 'time of symptom onset to procedure' in our population; in SAMMPRIS, only patients with symptom onset of no more than 30 days before enrollment were included.

This study has some limitations. First, included studies were mostly case series, retrospective, and with small sample sizes. Second, most studies lacked a control comparative arm (ie, medical treatment, stent,percutaneous transluminal angioplasty). The studies were conducted over a long period of time, which could have underestimated the effect given the substantial yearly improvement in balloons, devices, and techniques since 1980 to the present. Furthermore, the inclusion criteria were heterogeneous.The criteria included different definitions for SA, and for methodological details such as balloon inflation times and diameters. Although comparison of these results with previous distinguished studies such as SAMMPRIS is valuable, to reach a definite conclusion about the advantages of SA a large-scale randomized controlled clinical trial is needed to compare the safety and efficacy of SA, using standardized and contemporary techniques, with medical treatment. Ideally, a large-scale clinical trial with study arms of SA in addition to AMT versus AMT alone would be an appropriate choice. Finally, in some cases, a delayed angiogram may follow the initial angioplasty, leading to potential exclusion of challenging patients in studies.

Conclusions

Our systematic review and meta-analysis suggest submaximal angioplasty is an efficacious and safe therapeutic option in the treatment of patients with ICAD. Future clinical trials are warranted to establish the efficacy of submaximal angioplasty in patients with symptomatic ICAD compared with currently recommended methods.

References

Footnotes

  • Twitter @yagizyolcu

  • SMS and YUY contributed equally.

  • Contributors All authors (SMS, YUY, AN, AR, MA, MHM, WB, MB, and DFK) have made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting of the work or revising it critically for important intellectual content. SMS, YUY, and AA made substantial contributions to data collection. All authors have provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SMS made substantial contributions to the conception or design of the work; the acquisition, analysis and interpretation of data for the work; drafting of the work, provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. YUY made substantial contributions to the conception or design of the work; the acquisition, analysis and interpretation of data for the work; drafting of the work, provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AN made substantial contributions to the conception or design of the work; the acquisition, analysis and interpretation of data for the work; drafting of the work, provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AR made substantial contributions to the conception or design of the work; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MA made substantial contributions to the conception or design of the work; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MHM has made substantial contributions to analysis and interpretation of data for the work; provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. WB made substantial contributions to the conception or design of the work; revised the manuscript critically for important intellectual content, provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MB revised the manuscript critically for important intellectual content, has provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DFK made substantial contributions to the conception or design of the work; revised the manuscript critically for important intellectual content, provided final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data could be made available upon request from the corresponding author.