Effect of percutaneous transluminal angioplasty and stenting vs aggressive medical management on Risk of Stroke and Death in Patients with stroke or intracranial atherosclerotic stenosis: a systematic review and meta-analysis

DOI: https://doi.org/10.21203/rs.3.rs-2506683/v1

Abstract

Background: There are currently two treatment strategies mainly for high-risk patients: percutaneous transluminal angioplasty and stenting (PTAS) and aggressive medical management (AMM). However, the choice between PTAS or AMM remains controversial for patients with stroke or intracranial atherosclerotic stenosis (ICAS).

Methods: The investigators searched PubMed, Web of Science, Embase, Scopus,  and Cochrane library databases. Randomized controlled trial (RCT) comparing the PTAS and AMM for patients with stroke or ICAS were selected. RevMan 5.3 was used to analyze the results and risk of bias. The primary endpoints are stroke and death within 30 days after enrollment, or ischemic stroke in the territory of the qualifying artery beyond 30 days, and entire follow-up endpoints. The secondary outcomes were the disabling or fatal stroke, and incidence of death within 3 years.

Results: Four studies, 989 patients were included in this article. The AMM group was superior in the entire follow-up endpoint (OR: 0.56; 95% CI: 0.40, 0.79). The AMM also better in primary endpoint within 30 days (OR: 0.32; 95% CI: 0.17, 0.61). There was no significant difference beyond 30 days (OR: 1.08; 95% CI: 0.63, 1.86). The remaining outcomes, such as stroke and death, were not significantly different (P>0.05).

Conclusion: This meta-analysis shows AMM is significantly more effective than PTAS in subjects with ICAS because of the high rate of periprocedural OR: 0.32; 95% CI: 0.17, 0.61) and entire follow-up (OR: 0.56; 95% CI: 0.40, 0.79) stroke from PTAS and the fact that PTAS offers no benefit over AMM beyond 30 days (OR: 1.08; 95% CI: 0.63, 1.86).

Introduction

Stroke is the second-leading cause of death and is the third-leading cause of death and disability combined in worldwide[1]. A systematic analysis noted that Stroke and ischaemic heart disease were the leading causes of death in China in 2017[2]. ICAS is a major cause of stroke and is associated with a high risk of recurrent stroke[35]. In patients with transient ischemic attack (TIA) or stroke, recurrent stroke is at high risk of occurrence even with aspirin and management of vascular risk factors[6, 7]. Therefore, the treatment options are crucial to reduce mortality and stroke recurrence.

Since it is still difficult to avoid stroke recurrence in patients treated with conventional medications and risk factor management, more alternative therapies have been developed[8]. There are currently two treatment strategies mainly for high-risk patients: percutaneous transluminal angioplasty and stenting (PTAS) and aggressive medical management (AMM, combination antiplatelet therapy and intensive medical management). Some studies reported that PTAS benefits for patients[914]. However, the choice between PTAS or AMM remains controversial for patients with stroke or ICAS[8]. Although several published RCTs provide ideas, the comparison of PTAS and AMM remains controversial due to different conclusions and the lack of high-quality systematic reviews and meta-analysis. This systematic review and meta-analysis only included high-quality RCTs published before October 1, 2022, and focused on the effects of PTAS compared with AMM.

Methods

Study Selection

This systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The whole retrieval process is shown in Fig. 1. Our research conducted a systematic search on the literature published before October 1, 2022 in PubMed, Web of Science, Scopus, Embase and Cochrane library databases. The search terms are as follow: (balloon angioplasty or PTA or percutaneous transluminal angioplasty or angioplasty) AND (Stenting or stent) AND (cerebral ischemia or strok or cerebral ischemia or intracranial arteriosclerosis or intracranial artery) AND (Randomized Controlled Trial OR RCT OR randomized OR random OR Controlled Trials), all restricted to title, abstract, and keywords. After achieving the preliminary retrieval results, researchers screened literature according to the title and abstract independently. Any disagreement was resolved by members that are not involved in study selection. All references were managed via EndNote X9 (Thomson Reuters, NY, USA).

Eligibility Criteria

Studies in this meta-analysis must meet the following criteria: RCT, percutaneous angioplasty and stenting (PTAS) compared with aggressive medical management (AMM), patients undergo cerebral ischemia or stroke. In addition, studies with the following characteristics were excluded: not RCT, patients < 18 years, registered but unpublished research, lack of data required for meta-analysis, no comparisons of angioplasty with stent, and unclear grouping.

Risk of Bias Assessment

Based on the Cochrane Collaboration Tool, investigators analyzed the risk of bias of the included studies independently and obtained the overall bias of the studies, which were evaluated with high risk, low risk and unclear. The bias evaluated included: Random sequence generation (selection bias), Allocation concealment (selection bias), Blinding of participants and personnel (performance bias), Blinding of outcome assessment (detection bias), Incomplete outcome data (attrition bias), Selective reporting (reporting bias), Other bias (baseline imbalance, Conflict of interest, etc.). If the results were different, another investigator was required to decide. Assessments were stored and managed in RevMan 5.3(Review Manager. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.).

Data Extraction

All data extraction work was done independently. If the results could not be negotiated due to differences in results, the other researcher needs to be asked to reach a consensus. We extracted research data from included studies and stored them into Microsoft Excel Collection Data Sheets. Evaluated Study and Patients’ Characteristics was listed in Table 1.

Table 1

Summary of the Characteristics of studies and patients in 4 eligible RCTs

Author Yr

Group (n)

Ages, mean ± SD, Yr

Gender, M/F

Hypertension, n

History of coronary artery disease, n

History of stroke (not qualifying event), n

Qualifying event, Stroke/TIA

Smoker, Never/Former/Current

Gao et al. 2022

PTAS (176)

56.7 ± 9.4

128/48

117

19

ND

89/87

96/39/41

 

AMM (182)

55.9 ± 9.8

135/47

125

19

ND

105/77

94/38/50

Miao et al. 2012

PTAS (36)

53.42 ± 13.55

24/12

23

3

ND

7/29

ND/ND/21

 

AMM (34)

49.18 ± 9.29

25/9

15

5

ND

8/26

ND/ND/19

Zaidat et al. 2015

PTAS (58)

61.8 ± 12.28

41/17

49

10

ND

36/24

25/22/11

 

AMM (53)

61.8 ± 12.82

32/21

43

12

ND

34/22

24/17/12

Derdeyn et al. 2014

PTAS (224)

61.0 ± 10.7

127/97

200

47

60

142/82

90/79/54

 

AMM (227)

59.5 ± 11.8

145/82

203

59

58

152/75

78/80/69

PTAS: percutaneous angioplasty and stenting ; AMM: aggressive medical management; RCT: randomized control trial; ND: not declared; M: male; F: female; IQR: interquartile range; SD: standard deviation; TIA: transient ischemic attack; Yr: year;

Outcomes

The primary outcome of this systematic review consisted of stroke and death within 30 days after enrollment, or ischemic stroke in the territory of the qualifying artery beyond 30 days and entire follow-up endpoints. The secondary outcomes were the stroke in the same territory within 2 and 3 years, disabling or fatal stroke, and incidence of death within 3 years.

Statistical Analysis

RevMan 5.3 was used for all data analysis in this study. We reported the odds ratios (OR) and 95% confidence interval (CI). And we used the Mantel-Haenszel method for analysis. Heterogeneity was assessed before meta-analysis of included studies. When the heterogeneity test P < 0.05 or I2 > 50%, the random model is used, otherwise the fixed model is selected.

Results

Literature Search Findings

Our research has been registered with PROSPERO; the registration number is CRD42022362266. We searched in PubMed, Web of Science, Cochrane library, Scopus, and Embase databases on the title, abstract, and keywords of the literature, and 913 articles were obtained (Databases n = 900, Registers n = 30). We used EndNote X9 to find duplicates, and exclude non-clinical studies. Then, we reviewed the abstract and title, 90 clinical studies were included in the final review phase. We screened the full text of these studies, and 4 included studies were finally determined (Not RCT: 7; No comparisons of angioplasty with stent: 71; Study protocol: 8). Literature Search Findings is shown in PRISMA_2020_flow_diagram (Fig. 1).

Study and Patient Characteristics

We summarized the study and patient characteristics in Table 1, including author, group, age, gender, medical history (Hypertension, coronary artery disease, and stroke), qualifying event, and smoker. All studies reported the age, sex, hypertension, smoker, and history of coronary artery disease of the patients. Only one study did not reported history of stroke (not qualifying event)[14].

Risk of Bias Assessment and Study Quality

We used RevMan 5.3 to summarize the bias of the included studies in Fig. 2,3. It was expressed as high risk, low risk, and unclear. For the included RCTs, design of the blinding of participants and personnel was considered difficult. Only one study defined high risk explicitly reported blinding of outcome assessment[14].

Primary outcome: entire follow-up endpoint

Four studies[8, 1416] reported the entire follow-up endpoint with a sample size of 989. The pooled OR (95% CI) was 0.56 (0.40, 0.79) in favor of AMM group, heterogeneity test I2 = 49% was not significant (Fig. 4). These results reached statistical difference(P = 0.0009).

Primary outcome: within and beyond 30 Days after enrollment events

Three studies[8, 15, 16] reported the primary endpoint within 30 Days after enrollment with a sample size of 538. The pooled OR (95% CI) was 0.32 (0.17, 0.61) in favor of AMM group, heterogeneity test I2 = 0% was not significant (Fig. 5). These results reached statistical difference(P = 0.0005).

Two studies[8, 16] reported the primary endpoint beyond 30 Days after enrollment with a sample size of 427. The pooled OR (95% CI) was 1.30 (0.58, 2.92), heterogeneity test I2 = 0% was not significant (Fig. 6). The difference in results was not significant (P = 0.52).

Secondary outcomes: stroke events

Two studies[14, 15] reported the disabling or fatal stroke with a sample size of 543. The pooled OR (95% CI) was 0.75 (0.41, 1.36), heterogeneity test I2 = 0% was not significant (Fig. 7A). The difference in results was not significant (P = 0.34).

Secondary outcomes: incidence of death

Two studies[8, 14] reported the disabling or fatal stroke with a sample size of 770. The pooled OR (95% CI) was 0.73 (0.37, 1.46), heterogeneity test I2 = 49% was not significant (Fig. 7B). The difference in results was not significant (P = 0.37).

Discussion

This systemic review and meta-analysis in patients presenting with stroke and ICAS demonstrated that primary end points in the AMM group were superior to PTAS group in entire follow-up and within 30 days, and there was no significant difference beyond 30 days. In addition, there was no significant difference in either disabling or fatal stroke or mortality between the two groups.

Our results showed that AMM provided benefits in entire follow-up and within 30 days compared with PTAS. This is similar to the results of several studies[8, 17] and confirms that AMM should be considered first for patients with ICAS rather than PTAS[18]. In entire follow-up and within 30 days, AMM is superior to PTAS perhaps associated with unstable plaque, which increases the risk of adverse events such as distal embolism after stenting[19, 20]. Chimowitz et al.[17] included patients with TIA or nondisabling stroke due to 70–99% stenosis of the diameter of the large intracranial arteries confirmed by angiography within 30 days before enrollment. Similar to the conclusions of this study, AMM provided more benefits for patients than PTAS within 30 days. The difference is that the AMM effect remains superior to PTAS beyond 30 days, and there were no statistically significant differences in any of the outcomes beyond 30 days in this study. The primary endpoint was also assessed in a multicenter, open-label RCT by Gao et al[8]. Similar to this study, there were no statistical differences in outcomes beyond 30 days. Differences in conclusions may be attributable to characteristics in patients, other biases are equally non-negligible. Multicenter studies imply a larger number of participants and operators, which may lead to inconsistencies in their experience with stenting. The importance of experience is suggested by the association of high-volume centers with a lower risk of complications[2124]. Besides, the outcome of the PTAS group may be related to the quality and limitations of the stent device, and the iterations of stent may enhance the safety and success.

In addition, the selection of patients may also lead to different results. For example, Gao et al.[8] used magnetic resonance imaging (MRI) and computed tomography for screening patients in addition to applying angiography, thus excluding those with perforator stroke alone without artery-to-artery embolism or distal hypoperfusion. This appears to identify high-risk patients, select patients for intracranial PTAS and reduce the occurrence of perforator occlusion during stent implantation, to which several studies have attributed perioperative embolism after stenting procedures[2529]. For the difference between short-term and long-term outcomes, this may be related to the timing of treatment. Early stenting is associated with a higher risk of complications, and longer time intervals have a reduced risk of complications[14, 17, 23]. In addition, the effect of PTAS may vary depending on the stage of the stroke.

A meta-analysis published in 2017 compared the effects of applying PTAS and drug therapy to patients with Symptomatic Intracranial Atherosclerotic Disease[30]. The results showed that medical therapy was superior to PTAS within 30 days, and there was no statistical difference between those beyond 30 days, which was similar to the results of this study. However, the authors included only 3 eligible RCTs with 581 participants, which may affect the stability of the conclusions. Although PTAS has a high short-term complication rate, based on the importance of extending the time window for endovascular embolization and improving reperfusion, PTAS might be used as a salvage treatment for failed mechanical embolization of large arterial occlusions in the anterior circulation[3133].

This meta-analysis has the following limitations. Firstly, the number of studies included is limited because there are fewer RCTs published in English and related to our research topics, and we have excluded all retrospective studies. Secondly, heterogeneity is a difficult part of meta-analysis to ignore, with factors such as patient characteristics, inclusion and exclusion criteria contributing to heterogeneity. However, in the present study, the results of the heterogeneity test were acceptable. In addition, an included RCT had only 16 participants, so the risk of bias is existed.

Conclusion

This meta-analysis shows AMM is significantly more effective than PTAS in subjects with ICAS because of the high rate of periprocedural OR: 0.32; 95% CI: 0.17, 0.61) and entire follow-up (OR: 0.56; 95% CI: 0.40, 0.79) stroke from PTAS and the fact that PTAS offers no benefit over AMM beyond 30 days (OR: 1.08; 95% CI: 0.63, 1.86).

Abbreviations

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-analyses

OR

Odds ratio

RCT

Randomized Controlled Trial

TIA

transient ischemic attack

PTAS

percutaneous transluminal angioplasty and stenting

AMM

aggressive medical management

CI

confidence interval

MRI

magnetic resonance imaging

ICAS

intracranial atherosclerotic stenosis.

Declarations

Funding

This study was supported by Administration of Traditional Chinese Medicine of Guangdong Province of China (grant no. 20211157).  The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest Disclosure

This article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors’ contributions

Z.Y.L. and M.Q.P. contributed equally to this study and shared first authorship. They helped design the study, conduct the study, analyze the data, and write the manuscript. Y.B.L. and X.X.B. helped conduct the study, analyze the data, and write the manuscript. J.C. is corresponding author, mainly responsible for the inspection of study, and approval of the article finally.

Availability of Data and Materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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